Autosomal Dominant Anhidrotic Ectodermal Dysplasia with Immunodeficiency (AD-EDA-ID)
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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.
Characteristic Clinical Features of Ectodermal Dysplasia (EDA) and Beyond
The first case of AD-EDA-ID with heterozygous NFKBIA mutation was discovered in 2003 (Courtois et al. 2003). Unlike XL-EDA-ID, almost all patients reported with AD-EDA-ID mutations presented with EDA early in life. Abnormalities of embryonic ectodermal tissues are evident during the physical examination (hair, teeth, nail, sweat glands) as NF-κB activation is an essential step in their development via ectodysplasin/ectodysplasin signaling pathway. The most apparent signs of EDA are anhidrosis or hypohidrosis due to lack of functional sweats glands followed by teeth abnormalities (i.e., conical shaped), sparse hair, and mental retardation, respectively. Other developmental features like neurological deficits, osteopetrosis, and lymphedema have not reported. Lymph nodes are usually small or absent, mainly in patients with missense mutations. Autoimmunity is not uncommon which can present as lupus, juvenile idiopathic arthritis, autoimmune thyroiditis, or autoinflammation. Patients can present with recurrent diarrhea and/or colitis.
Patients present with broad-spectrum severe infections (viruses, bacteria, and fungi) at an early age. Patients commonly present with recurrent upper respiratory tract infections including pneumonia; however, severe sepsis and meningitis also occur. Mycobacterial infections have been reported in a few cases. Fungal infections in the form of chronic mucocutaneous candidiasis (CMC) and pulmonary pneumocystosis have been described. While they still occur, viral infections caused by rotavirus, respiratory syncytial virus (RSV), cytomegalovirus (CMV), parainfluenza virus, norovirus, and sapovirus are less frequent. Patients are usually unable to mount fever due to impaired of the IL-1R and TLR signaling.
The defect in innate immunity is variable and not well characterized. Monocytes and neutrophils appear normal in count and function. Unlike XL-EDA-ID, NK cell counts and function are also generally within normal range except in three reported cases; however, functional studies were reported only in one case (Boisson et al. 2017). There are no reports of innate lymphoid cell counts or proportions. The defect in adaptive immunity is less variable compared to innate immunity. The most observed defect is T lymphocytosis with an abundance of naïve CD4 and CD8 T cells and decreases memory T-cell fraction. The proportion of γ/δ T cells is low or absent. Limited evidence shows impaired polarization of naïve CD4 T cells to Th1 and Th17. T-cell proliferation with mitogens phytohemagglutinin A (PHA) or concanavalin A (ConA) is generally intact. T-cell proliferation to antigen stimulation was variable from intact to absent in a couple patients. T-cell proliferation with α-CD3 alone was impaired in almost all the cases; however, adding α-CD28 restored the proliferation of these T cells. The B-cell compartment is significantly affected. Total B cells are typically high but can be normal. Nonetheless, switched memory B cells are either low or absent. Immunoglobulin levels are almost always abnormal and vary between high IgM with or without low IgG/IgA and low IgM with or without high IgG/IgA. Dysgammaglobulinemia is common with impaired antibodies response to vaccine antigens.
Diagnosis and Laboratory Testing
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.