NEMO Mutations in 2 Unrelated Boys With Severe Infections and Conical Teeth

Abstract

ABSTRACT. X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency is a developmental and immunologic disorder caused by mutations in nuclear factor-B essential modulator (NEMO), which is essential for nuclear factor-B activation. Early in life, affected boys present a typical appearance, with hypotrichosis or atrichosis, hypohidrosis or anhidrosis, and hypodontia or anodontia with conical incisors. They are also susceptible to various microorganisms, mostly pyogenic bacteria and mycobacteria. Here we report 2 unrelated boys, aged 6 and 11 years, who have novel mutations in NEMO and present conical incisors and hypodontia as their sole and long-unrecognized developmental anomaly. One child had isolated recurrent pneumococcal disease, whereas the other had multiple infections. Our ABBREVIATIONS. XL-EDA-ID, X-linked anhidrotic ectodermal dysplasia with immunodeficiency; NF-B, nuclear factor-B; NEMO, nuclear factor-B essential modulator; TNF, tumor necrosis factor; IL, interleukin; Ig, immunoglobulin; Hib, Haemophilus influenzae type b. X -linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a rare congenital disease, characterized by abnormal development of ectoderm-derived skin appendages and susceptibility to infectious diseases. [1][2][3][4][5][6][7][8][9][10][11][12] Most affected individuals are male. In early childhood, they generally present multiple overt developmental anomalies, such as hypohidrosis or anhidrosis resulting in intolerance to heat, hypotrichosis or atrichosis, and hypodontia or anodontia with conical incisors, resulting in a typical facial appearance. A small number of patients also present with osteopetrosis and lymphedema. More than half of the known patients died from severe infections, generally caused by pyogenic bacteria and poorly pathogenic mycobacteria. Paradoxically, the only anomaly that is found consistently during routine immunologic tests is an impaired antibody response to polysaccharide antigens. Various hypomorphic mutations have been found in nuclear factor-B (NF-B) essential modulator (NEMO), which encodes a critical component of the NF-B signaling pathway. The EDA phenotype results from impaired NF-B activation by the single ectodysplasin receptor. In contrast, immunodeficiency results from impaired NF-B activation by multiple immune receptors, such as members of the Toll-like receptor, interleukin (IL)-1 receptor, and tumor necrosis factor (TNF) receptor superfamilies and T/B-cell receptors. We report 2 unrelated boys who bear mutations in NEMO. Both experienced severe infectious diseases. Abnormal teeth were their sole developmental anomaly. CASE REPORTSPatient 1 is a 6.5-year-old white boy who was born to unrelated French parents. He had been hospitalized previously for 3 episodes of Streptococcus pneumoniae arthritis, affecting a knee at the age of 2 years, an ankle at 5 years, and a hip at 5.5 years. At 3 years, the patient was hospitalized for Haemophilus influenzae lobar pneumonia. No other unusually severe infections were ...

Immunity to Microbes: Lessons from Primary Immunodeficiencies

“…In contrast to S. pneumoniae, H. influenzae was not isolated from any of the IRAK-4-deficient patients described by Ku et al (61) and was associated with only a few cases of NEMO mutations (60,61).…”

“…The susceptibility of IL-1 receptor-associated kinase 4 (IRAK-4)-deficient patients to pneumococcal infections is extreme (23,38,61,70,86), and susceptibility of patients with PIDs due to defects in NF-B essential modulator (NEMO)-dependent NF-B activation (X-linked anhydrotic ectodermal dysplasia with immunodeficiency [XL-EDA-ID] and other milder phenotypes) (60,61,83,108) is also high but not extreme, as in IRAK-4-deficient patients. This demonstrates the relevance of innate immunity in protection against S. pneumoniae.…”

The Pathology of Mycobacterium tuberculosis Infection

“…9 Both TLRs and NOD2 signal through the NF-kB signaling pathway, and mutations in the leucine zipper domain of NEMO (IkB kinase-g), which is an activator of this pathway, have been associated with increased susceptibility to mycobacterial disease. 121 These mutations led to profound defects in interleukin (IL)-12 and secondary interferon (IFN)-g production in monocytes from these patients. 66 Internalized Mtb resides in a phagosome, where, in resting macrophages, the bacteria block maturation, lysosomal fusion, and acidification.…”

Alterations of the IKBKG locus and diseases: an update and a report of 13 novel mutations

“…A total of 13 mutations are located in exon 10 and the remaining 15 are scattered all along the IKBKG gene. Among the IKBKG mutations, 14 are missense, three nonsense, six frameshift, two splice-site mutations, and one is an in-frame deletion of five amino acids (c.811_828del; p.Glu271_A-la276del) [Ku et al, 2005] and one nonstop (c.1259A4G; p.X420TrpextX27) [Smahi et al, 2000]. In addition, one large duplication (c.3991850_674dup, 41 kb) has been reported, the effect of which on the open reading frame (ORF) has only been predicted (p.Ala174X) [Nishikomori et al, 2004].…”