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 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.

Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency

“…With appropriate therapy, the infection resolved, suggesting HSCT corrected enough of the immune deficiency. In contrast to our post-HSCT patients with IKBKB immune deficiency, Miot et al found that bacterial infections only recurred at > 6-months post-HSCT for NEMO deficiency in 2/27 patients [23]. We hypothesize that failure of HSCT to improve all aspects of innate and adaptive immune function after transplant, as shown by the number of ongoing serious bacterial and Mycobacterial infections and lack of protective specific antibody responses to vaccinations, could be because HSCT does not correct cells of non-hematopoietic origin important in the immune response that are also dependent upon IKK/NF-κB signaling.…”

“…In addition to infectious predisposition, patients with NEMO deficiency may present with autoimmunity (25%) and inflammatory conditions (most notably inflammatory bowel disease in 21%), features not described in either our cohort of IKBKB immune deficient patients nor in those with hypermorphic IκBα defects. As in patients with IKBKB immune deficiency, patients with NEMO deficiency commonly present with infections due to pyogenic bacteria (87%), Mycobacteria (44%), viruses (21%) and fungal and opportunistic pathogens (10%) [22] The median age at HSCT for a large cohort of NEMO deficient patients was 3.3 years old (range: 4.4 months -18.8 years), an age that is older compared to our cohort, suggesting NEMO deficiency may be a less severe immune deficiency relative to IKBKB immune deficiency [23]. NEMO deficiency also has a more variable immunologic phenotype, with hypogammaglobulinemia in only 24/41 (59%) and defects in specific antibody production in 18/28 (64%).…”

“…Unfortunately, and based on this limited dataset, we believe myeloablative conditioning may be required for engraftment in IKBKB immune deficiency. The largest and most recent study of HSCT in NEMO patients, however, did not find this to be necessarily true [23]. In their cohort of fifteen patients receiving classical myeloablative conditioning and thirteen patients receiving reduced intensity conditioning, the global engraftment rate was 93%, with similar survival rates and secondary graft failure rates, independent of conditioning regimen intensity.…”

“…We are unaware of any reports of hypomorphic IKBKB mutations producing a milder clinical phenotype, allowing clinicians to take a wait and see approach. HSCT for other disorders involving the IKK/NF-κB pathway have been previously described, including for hemizygous hypomorphic IKBKG mutations [23] and hypermorphic NFKBIA mutations [21]. In the cohort of fourteen IκBα gain of function patients reported by Boisson et al, eleven received HSCT, with only five survivors.…”

Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases

“…In parallel investigations, Cuchet-Lourenço et al (33) identified four patients with loss-of-function mutations in RIPK1 causing combined immunodeficiency and intestinal inflammation due to altered cytokine secretion and necroptosis of immune cells. Whereas these authors concluded that allogeneic HSCT may constitute a curative therapy, our studies suggest that RIPK1 plays a critical role in controlling cell death of the intestinal epithelium, and thus warrant awareness that HSCT might dampen intestinal inflammation but not rescue intrinsic intestinal phenotypes of human RIPK1 deficiency, similar to NF-kappa-B essential modulator deficiency (34). The exact triggers perturbing epithelial integrity in RIPK1 deficiency could not be fully determined in our studies or mouse models yet.…”