EDA-ID; HED-ID; Hypohidrotic ectodermal dysplasia with immunodeficiency; IkB-alpha gain of function

Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is a group of disorders characterized by ectodermal tissue (ED)-related abnormalities including conical teeth, decrease/absent sweat glands, fine sparse hair, and increase susceptibility to severe infections. The disorder is linked to abnormalities of activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways (Fig. 1). Normally, in the canonical pathway, NF-κB activation occurs once external stimuli activate IκB kinase (IKK) complex that constitutes of a heterodimer of the catalytic IKKα and IKKβ units and a regulatory IKKγ unit also called NF-κB essential modulator (NEMO). Activated IKK complex phosphorylates NF-κB inhibitor α (IκBα) at serine 32 and 36 residues and therefore promotes its ubiquitination and degradation. Subsequently, NF-κB transcription factor dimer (p50/RelA) is released from an inhibited state and translocated to the nucleus to activate target genes linked to inflammation. This pathway is triggered by several receptors (e.g., CD40, Toll-like receptor (TLR), T- and B-cell antigen receptor (TCR/BCR), and tumor necrosis factor α (TNF-α) receptor). In contrast, noncanonical activation of NF-κB pathway may occur with B-cell activating factor receptor (BAFFR), LTβR, and CD40 and will promote lymphorganogenesis by nuclear translocation of a second variant of NF-κB transcription factor dimer (p52/RelB). Interaction between these two pathways has been discovered through immune evaluation of patients with mutations in NFKBIA that result in deficiency IκBα.

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There are two forms of EDA-ID, X-linked (XL)(OMIM #300291) and autosomal dominant (AD) (OMIM #164008) EDA-ID. Mutations in IKBKG encoding NEMO are hemizygous, whereas gain-of-function (GOF) mutations in NFKBIA gene encoding IκBα are heterozygous. A mutation to NFKBIA gene leads to continued inhibition of NF-κB activation when the pathway is triggered.

Anhidrotic ectodermal dysplasia features are a helpful indicator for early diagnosis of AD-EDA-ID. It is almost observed in all cases of AD-EDA-ID. To clinically diagnose EDA, at least two of the following seven features need to be seen: (1) lessened skin pigmentation; (2) sparse or absent scalp and body hair; (3) reduced, absent, or malfunctioned sweat glands; (4) dark and wrinkled periorbital skin; (5) hypodontia, anodontia, or conically shaped front teeth; (6) low nasal bridge and small nose with underdeveloped alae nasi; and (7) frontal bossing with prominent supraorbital ridges.

Broad-spectrum infections, the absence of tonsils and lymph nodes, and autoimmune manifestations can be important clues for diagnosis.

Laboratory studies may include complete blood count (typically normal), lymphocyte enumeration (naïve lymphocytosis in T- and B-cell compartments with low to absent memory cells), immunoglobulin levels and vaccine titers (antibodies’ response postimmunization is always poor), and functional assay for T-cell proliferation (stimulated by mitogen, antigen, and interleukins). The definitive diagnostic tool for AD-EDA-ID is genetic testing for NFKBIA gene mutations (Ohnishi et al. 2012). In case of variant of unknown significance, molecular studies are recommended to evaluate IκBα expression and NFKB nuclear translocation (signaling of canonical and noncanonical NKFB pathways).

By 2018, 13 more cases have been described, and a scoring system with excellent genotype-phenotype correlation was proposed based on infections, ED-related abnormalities, antibody responses, lymphocyte counts, and memory subsets (Petersheim et al. 2018). The majority of patients had de novo nonsense (truncation mutation) or missense (point mutation) at or close to serine 32 and 36 residues. IκBα missense point mutations result in higher level of mutant protein with increased cytoplasmic sequestration and higher level of impairment of NF-κB (p50/RelA) than truncating mutations. Furthermore, missense mutations also affected the noncanonical NF-κB pathway supported by the molecular studies and absence of tonsils and lymph nodes in this cohort. Overall, patients with missense NFKBIA mutations had more severe disease.

It is recommended that AD-EDA-ID patients get immunized with conjugated and non-conjugated bacterial vaccines (e.g., Streptococcus pneumoniae, H. influenzae, and Neisseria meningitidis). Live vaccines including BCG should be avoided. If no response is mounted to vaccines, initiation of immunoglobulin replacement therapy (IgRT) is indicated. As patients are usually unable to mount fever, if an infection is suspected, early empirical intravenous antibiotics should be administered. It is highly recommended to initiate prophylaxis antibiotics against Pneumocystis jirovecii and Candida albicans with cotrimoxazole and an antifungal drug (e.g., fluconazole) (Kawai et al. 2012). In the event of mycobacterial infection, antimycobacterial treatment along with recombinant interferon γ (rIFN-γ) should be started. Hematopoietic stem cell transplantation (HSCT) has been attempted for patients with both missense (n = 6) and truncating mutations (n = 2) (Petersheim et al. 2018). In this small study, HSCT was partially successful. Half of the patients are alive after HSCT, and all patients with missense NFKBIA mutations continue to remain on IgRT for recurrent infection. The outcome of HSCT in one patient with truncating NFKBIA is excellent with no infections and off IgRT. However, another patient with truncating NFKBIA is doing well on IgRT without the need for HSCT. Therefore, the indication for HSCT in this complex group of AD-EDA-ID is unclear.