Autosomal Dominant Anhidrotic Ectodermal Dysplasia with Immunodeficiency Caused by a Novel NFKBIA Mutation, p.Ser36Tyr, Presents with Mild Ectodermal Dysplasia and Non-Infectious Systemic Inflammation
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Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized by hypohidrosis, dental abnormalities, sparse hair, and immunodeficiency. Autosomal dominant (AD)-EDA-ID, caused by a heterozygous mutation within NFKBIA, is very rare and its clinical features remain largely unknown. This study describes a patient with AD-EDA-ID harboring a novel NFKBIA mutation who presented with mild EDA and non-infectious systemic inflammation.
The clinical presentation of an AD-EDA-ID patient was described and immunological, genetic, and biochemical analyses were performed, with a focus on nuclear factor kappa B (NF-κB) activation.
The patient presented with symptoms of mild EDA-ID, namely sparse hair and hypohidrosis, although a skin biopsy confirmed the presence of sweat glands. There were no dental abnormalities. The patient also suffered from non-infectious inflammation, which responded to systemic corticosteroid therapy; however, the patient remained ill. Immunological analyses revealed reduced Toll-like receptor/IL-1 (TLR/IL-1) and tumor necrosis factor (TNF) receptor family responses to various stimuli. Genetic analysis identified a de novo heterozygous missense mutation, p.Ser36Tyr, in NFKBIA, resulting in defective NFKBIA degradation and impaired NF-κB activation. The patient was diagnosed with AD-EDA-ID and underwent hematopoietic stem cell transplantation. Engraftment was successful, with few signs of acute graft versus host disease. However, the patient suffered hemolytic anemia and thrombocytopenia, and died from a brain hemorrhage due to intractable thrombocytopenia.
AD-EDA-ID patients can present with mild ectodermal dysplasia and non-infectious inflammation, rather than with recurrent infections. Also, hematopoietic stem cell transplantation for AD-EDA-ID is still a clinical challenge.
KeywordsEDA-ID NFKBIA IκBα HSCT
We thank Takeda Pharmaceutical Inc. for kindly providing us with recombinant human IL-2. We also thank Dr. Jain for providing the recombinant human soluble CD40L and Dr. Utani for providing us with normal fibroblasts. We would like to thank Dr. Momoko Nishikori for help with the EMSA assay. This work was supported by Japan’s Ministry of Health, Labor and Welfare and Japan’s Ministry of Education, Culture, Sports, Science, and Technology.
Conflict of Interest
The authors report no actual or potential conflicts of interest.
- 7.Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67(6):1555–62. doi: 10.1086/316914.PubMedCrossRefGoogle Scholar
- 9.Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. 2008;122(6):1169 e16–77 e16. doi: 10.1016/j.jaci.2008.08.018.CrossRefGoogle Scholar
- 10.Ohnishi H, Miyata R, Suzuki T, Nose T, Kubota K, Kato Z, et al. A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. The Journal of allergy and clinical immunology. 2012;129(2):578–80. doi: 10.1016/j.jaci.2011.09.042.PubMedCrossRefGoogle Scholar
- 11.Lopez-Granados E, Keenan JE, Kinney MC, Leo H, Jain N, Ma CA, et al. A novel mutation in NFKBIA/IKBA results in a degradation-resistant N-truncated protein and is associated with ectodermal dysplasia with immunodeficiency. Hum Mutat. 2008;29(6):861–8. doi: 10.1002/humu.20740.PubMedCrossRefGoogle Scholar
- 12.McDonald DR, Mooster JL, Reddy M, Bawle E, Secord E, Geha RS. Heterozygous N-terminal deletion of IkappaBalpha results in functional nuclear factor kappaB haploinsufficiency, ectodermal dysplasia, and immune deficiency. The Journal of allergy and clinical immunology. 2007;120(4):900–7. doi: 10.1016/j.jaci.2007.08.035.PubMedCrossRefGoogle Scholar
- 14.Nishikomori R, Akutagawa H, Maruyama K, Nakata-Hizume M, Ohmori K, Mizuno K, et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood. 2004;103(12):4565–72. doi: 10.1182/blood-2003-10-3655.PubMedCrossRefGoogle Scholar