Immunodeficiency and disseminated mycobacterial infection associated with homozygous nonsense mutation of IKKβ⋆ (original) (raw)

2014, Journal of Allergy and Clinical Immunology

Immunodeficiency and disseminated mycobacterial infection associated with homozygous nonsense mutation of IKKb To the Editor: Nuclear factor kappa B (NF-kB) signaling is known to be important for host protection against infection. For activation, proteins of the NF-kB transcription factor must be released from constitutive interaction with inhibitory IkB proteins (IkBa, IkBb, and IkBε), which sequester NF-kB complexes in the cytoplasm. This occurs through phosphorylation and degradation of IkB proteins by the upstream IkB kinase (IKK) complex, for example, following stimulation of cell surface receptors. The IKK complex consists of 2 catalytically active kinases, IKKa and IKKb, and the regulatory subunit IKKg, also known as NF-kB essential modulator (NEMO). In the canonical pathway of NF-kB activation, IkBa undergoes IKKb-dependent phosphorylation and ubiquitin-mediated degradation, liberating the NF-kB heterodimer, which then translocates to the nucleus. 1 Mutations in 2 proteins of the NF-kB signaling pathway, NEMO and IkBa, have been described in humans and result in immunodeficiency (ID), usually associated with ectodermal dysplasia (EDA). Hypormorphic hemizygote NEMO mutations cause X-linked EDA-ID, while hypermorphic IkBa mutations lead to an autosomal-dominant EDA-ID. 2-4 Affected individuals are susceptible to severe infections with pyogenic bacteria and mycobacteria and in some cases opportunistic and viral pathogens. 5 In addition, an autosomal-recessive mutation in IKKa has been associated with an in utero lethal Cocoon syndrome characterized by multiple fetal malformations. 6 Here, we report an 18-month-old female, second child of first-degree consanguineous parents from the Arabian Peninsula (see Fig E1, A, in this article's Online Repository at www. jacionline.org), who presented at age 2 months with omphalitis and delayed separation of the umbilical cord, necessitating surgical removal. At age 3 months, she developed Salmonella sepsis and subsequently suffered severe recurrent infections caused by a range of organisms including Acinetobacter, Enterobacter, Stenotrophomonas, and Achromobacter species, rotavirus, and Candida. Chronic diarrhea and a generalized maculopapular rash were persistent from the neonatal period. Disseminated BCGosis was diagnosed from skin and gut biopsies, and antimycobacterial treatment started at age 4 months. Her family history was significant for a brother who had died at age 1 month from E coli sepsis and meningitis. In addition, 3 paternal grand uncles had died in infancy with short febrile illnesses. At the age of 18 months, our patient had conical teeth, hepatosplenomegaly, and a severe skin rash (Fig 1, A and B). This was confirmed to be persistent BCGosis on skin biopsy showing a mixed inflammatory infiltrate and possible epithelioid granuloma formation (Fig E1, B), with acid-fast bacilli visible and a PCR positive for DNA of Mycobacterium tuberculosis complex, but negative for the esat-6 gene. Initial immunology