Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), X-linked
X-linked recessive EDA-ID (OMIM # 300291) is an immune deficiency with hypohidrotic ectodermal dysplasia caused by hypomorphic hemizygous mutations in IKBKG which encodes IKK-gamma/NF-kappa-B essential modulator (NEMO).
The NF-B signaling cascade is comprised of transcription factors that are normally sequestered in an inactive state in the cytoplasm. They are held in an inactive state through their interaction with IkB inhibitors. In response to a variety of immune and inflammatory stimuli, the IkB molecules become phosphorylated by an IkB kinase (IKK) core complex on two critical serine residues. This is a prerequisite to recognition by UBE2D3 leading to polyubiquitination and subsequent proteasomal degradation. This releases the NF-kB transcription factors and allows them to translocate into the nucleus where they initiate distinct profiles of gene expression depending on the cell type. NEMO/IKK-gamma is the regulatory subunit of the IKK core complex which also includes two kinases, IKK-alpha and IKK-beta, that is, responsible for phosphorylating the IkB inhibitors and releasing the transcription factors. The clinical manifestations of X-linked EDA-ID are characterized by hypomorphic mutations in the NEMO gene that impair NF-kB signaling in a wide variety of cell types.
The 23-kb human IKBKG gene is composed of ten exons with four alternative noncoding first exons on the human X-chromosome (Xq28). It is located in a region with a sequential duplication comprising a partial nonfunctional truncated pseudogene copy. Human IKK-gamma is a 419-amino acid protein with a predicted molecular weight of 48 kDa composed of two coiled-coil regions (CC1 – aa 100–194, CC2 – aa 260–292), a UBAN (ubiquitin binding in ABIN and NEMO proteins) domain, a leucine zipper (LZ) domain (aa 322–343), a proline-rich region, and a zinc finger (ZF) domain (aa 389–419) (Maubach and Naumann 2017). The activity of NEMO depends on its dimerization and its ability to interact with linear or K63-linked polyubiquitin chains. NEMO is normally recruited to polyubiquitin scaffolds assembled by upstream signaling events which in turn facilitates the recruitment, phosphorylation, and activation of the catalytic IKK subunits, IKK-alpha and IKK-beta, by TAK1 (TGF-beta activated kinase 1), which is also recruited concomitantly to the ubiquitin scaffolds (Israël 2010). This allows the kinase subunits to phosphorylate IkB inhibitors leading to their proteasomal degradation and inducing nuclear translocation of NF-kB transcription factors.
XR-EDA-ID caused by hypomorphic NEMO mutations was first described in 2000 (Zonana et al. 2000). Up to 100 male patients have been reported with more than 40 different mutations leading to impaired NEMO function. All known X-linked EDA-ID causing hypomorphic mutations either impair (1) protein expression, or (2) protein folding, or (3) polyubiquitin binding of NEMO, all essential for NEMO activation (Hubeau et al. 2011). Mutations span the entire NEMO gene and the variety and severity of clinical manifestations including infectious susceptibilities, auto-inflammatory diseases, and ectodermal dysplasia is strongly related to which specific NEMO protein domains are affected (Fusco et al. 2015). For example, mutations in the NEMO ZF domain causes a severe impairment in humoral immunity and dendritic cell function due to a specific impairment in c-Rel activation in response to CD40 (Temmerman et al. 2016). Mutations in the CC2 domain have no effect on protein expression but lead to a loss in the oligomer stability thereby altering IKK complex assembly which reduces TNF-alpha and LPS-induced NF-kB activation in B and T cells (Vinolo et al. 2006).
NF-kB activation is down-stream of numerous cell surface receptor families involved in innate and adaptive immunity including B cell receptor (BCR), T cell receptor (TCR), tumor necrosis factor (TNFR), Toll (TLR), and interleukin-1 receptor superfamilies. The development of ectodermal tissues is associated with the ectodysplasin receptor which is homologous to members of the TNF receptor superfamily. The various clinical manifestations of XR-EDA-ID result from impaired NF-kB signaling via these signaling pathways.
Common immune defects include variable defects in T cell proliferation, antibody deficiency, impaired antibody response to polysaccharide, and impaired NK cell cytotoxicity (Kawai et al. 2012; Nishikomori et al. 2004).
Affected patients suffer from bacterial sinopulmonary and invasive infections, mostly caused by pyogenic bacteria such as S. pneumoniae, S. aureus, and H. influenza and mycobacteria (Döffinger et al. 2001; Carrol et al. 2003; Picard et al. 2011). This is due to impaired functioning of innate immunity receptors such as TLRs and IL-1Rs and poor serum-antibody response to polysaccharide antigens (Ku et al. 2005). Pneumocystis jiroveci pneumonia has also been reported. Severe herpes virus infections have been reported may be due to the deficient natural killer cell cytotoxicity (Orange et al. 2002). Some patients present with a hyper IgM phenotype due to impaired co-stimulation by CD40 (Jain et al. 2004). Autoimmune and inflammatory diseases including hemolytic anemia, arthritis, and inflammatory bowel disease-like colitis have also been described (Mizukami et al. 2012). Osteopetrosis and lymphedema occurs in a severe subset of patients (Dupuis-Girod et al. 2002). In addition to immune defects, there are varying degrees of ectodermal dysplasia including conical teeth, fine sparse hair, and absence of sweat glands due to impaired NF-kB activation via the ectodysplasin/EDAR signaling pathway (Courtois and Israël 2011).
Laboratory evaluation should include quantitative immunoglobulins, measurement of vaccine antibody titers, functional analysis of NK cells, and Toll-like receptor assays. Patients can have low IgG but elevated IgM and IgA. Vaccine antibodies should be checked as antibody responses to polysaccharide antigens are often reduced. There is usually a deficiency of NK cell cytotoxicity. There is decreased inflammatory cytokine production from peripheral blood mononuclear cells after stimulation with TLR ligands. Sequencing of the gene for IKBKG will confirm the diagnosis. The presence of a NEMO pseudogene makes it difficult to perform genetic analysis using genomic DNA; the mutation should be identified by sequencing analysis of NEMO cDNA.
Patients should receive immunoglobulin replacement therapy (Perez et al. 2017). Prophylactic antibiotics should be considered for patients who continue to have infections despite immunoglobulin replacement. Vaccination with BCG should be avoided (Karaca et al. 2016). Hematopoietic stem cell transplantation should be considered in patients with a severe clinical immunodeficiency phenotype. A recent review of HSCT in 29 patients with hypomorphic IKBKG/NEMO mutations reported a global survival rate of 74% at a median follow-up after HSCT of 57 months (Miot et al. 2017). Preexisting mycobacterial infection and colitis were associated with poorer HSCT outcome. Critical genetic and immune studies aimed at identifying patients with NEMO deficiency at risk of mycobacterial infection are needed (Chandrakasan et al. 2017). HSCT will not correct the ectodermal dysplasia seen in patients.
- Vinolo E, Sebban H, Chaffotte A, et al. A point mutation in NEMO associated with anhidrotic ectodermal dysplasia with immunodeficiency pathology results in destabilization of the oligomer and reduces lipopolysaccharide and tumor necrosis factor-mediated NF-kappa B activation. J Biol Chem. 2006;281(10):6334–48.CrossRefPubMedGoogle Scholar