Anhidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID), Autosomal-Dominant
Autosomal-dominant EDA-ID (OMIM # 612132) is an immune deficiency with ectodermal dysplasia caused by germline heterozygous gain-of-function mutations in NFKBIA which encodes IkB-alpha.
The NF-kB signaling cascade is comprised of transcription factors that are normally sequestered in an inactive state in the cytoplasm through an association with inhibitory proteins such as IkB-alpha. Signaling through a variety of cell surface receptors involved in innate (TLRs, IL-1Rs, TNFRs) and adaptive (TCR and BCR) immunity triggers the phosphorylation of two key serine residues (S32 and S36) leading to its dissociation and subsequent proteasomal degradation. Once free from inhibition, NF-kB transcription factors are free to translocate to the nucleus and initiate cell-specific gene expression programs. Autosomal-dominant EDA-ID is associated with gain of function mutations in NFKBIA that reduce the degradation of IkB-alpha, thus impairing NF-kB signaling.
Autosomal-dominant EDA-ID was first described in 2003 (Courtois et al. 2003). To date only 14 patients with 11 mutations have been described in the literature (Boisson et al. 2017). All mutations associated with autosomal-dominant EDA-ID enhance the inhibitory capacity of IkB-alpha to block NF-kB activation by preventing its phosphorylation on S32 and S36 and subsequent degradation. Mutations belong to one of two groups: (1) missense mutations (point mutations) affecting S32, S36, or neighboring amino acids and (2) nonsense mutations (truncation mutations) that lead to the production of a mutant protein that skips S32 or S36 limiting its ability to be degraded (Petersheim et al. 2017). IkB-alpha point mutations were shown to accumulate at higher levels compared with truncation mutations in transfected cells and are associated with more severe disease and greater impairment of NF-kB signaling in patient cells.
Leukocytes from patients with autosomal-dominant EDA-ID have impaired Toll/interleukin-1 receptor (TIR), tumor necrosis factor receptor (TNFR1), and CD40 responses to stimuli. T-cell function mediated through TCR engagement is impaired. Most patients also had abnormally large total B-cell numbers but with a reduction or absence of memory B cells. Dysgammaglobulinemia was often detected, and patients had only low levels or no antibodies to vaccine antigens. Impaired NF-kB-mediated responses in innate and adaptive immune cells lead to a clinical phenotype consisting of multiple, severe infections caused by bacteria, fungi, and viruses beginning in early infancy.2 Bacterial infections include upper respiratory infections and pneumonia due to Klebsiella, Pseudomonas aeruginosa, or Haemophilus influenza and sepsis or meningitis due to Streptococcus or Staphylococcus aureus. Three patients developed mycobacterial infection caused by the BCG vaccine. Multiple patients suffered chronic mucocutaneous candidiasis and severe viral infections caused by rotavirus, norovirus, parainfluenza virus, RSV, and CMV. The majority of patients also presented with recurrent diarrhea and/or colitis without a clear inflammatory or infectious cause. Lastly, 13 of the 14 patients had varying presentations of anhidrotic ectodermal dysplasia including sparse hair, abnormal or missing teeth, and inability to sweat.
Laboratory evaluation should include quantitative immunoglobulins, measurement of vaccine antibody titers, flow cytometry for B-cell subpopulations, T-cell proliferation to specific antigens, and Toll-like receptor assays. Sequencing of the gene for NFKBIA will confirm the diagnosis.
The outcome and treatment of all 14 patients has been reported.2 One patient died prior to 1 year of age. The 11 remaining patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) to correct the underlying hematological abnormalities of which 6 died after HSCT from bacterial sepsis (n = 3), progressive neurodegenerative disease (n = 1), acute respiratory distress (n = 1), or cerebellar hemorrhage (n = 1). Of the five cases who underwent successful HSCT, all still have the EDA phenotype and four still have persistent partial immunodeficiency and are on intravenous immunoglobulin (IVIG) replacement therapy due to engraftment difficulties. For the two remaining patients without HSCT, both patients are on IVIG therapy and one has been receiving anti-tuberculosis treatment, recombinant IFN-gamma therapy as long-term anti-mycobacterial treatment, and antibiotic prophylaxis. The published cases suggest that HSCT is a high-risk undertaking that requires further investigation.
- Petersheim D, Massaad MJ, Lee S, et al. Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. J Allergy Clin Immunol. 2017;143:1060.e3. Pii: S0091-6749(17)30984-3Google Scholar