A number sign (#) is used with this entry because of evidence that immunodeficiency-33 (IMD33) is caused by hemizygous mutation in the gene encoding NF-kappa-B essential modulator (NEMO, or IKBKG; 300248) on chromosome Xq28.

Hemizygous mutation in the IKBKG gene can also cause the X-linked recessive disorder ectodermal dysplasia and immunodeficiency-1 (EDAID1; 300291).

Heterozygous mutation in the IKBKG gene results in X-linked dominant incontinentia pigmenti (IP; 308300) in females.

Immunodeficiency-33 (IMD33) is an X-linked recessive disorder that affects only males. It is characterized by early-onset severe infections, usually due to pneumococcus, H. influenzae, and atypical mycobacteria, although other organisms have also been detected. Immunologic investigations may show variable abnormalities or may be normal. Disturbances include dysgammaglobulinemia with hypogammaglobulinemia, decreased IgG2, aberrant levels of IgM and IgA, and decreased class-switched memory B cells. There is often poor, but variable, response to vaccination; in particular, most patients do not develop antibodies to certain polysaccharide vaccines, notably pneumococcus. Other immunologic abnormalities may include impaired NK cytotoxic function, impaired cytokine production upon stimulation with IL1B (147720) or TNFA (191160), low IL6 (147620), low IL12 (see 161561), and decreased IFNG (147570). Patients do not have overt abnormalities of T-cell proliferation, although signaling pathways, such as CD40LG (300386)/CD40 (109535), may be disturbed. There is heterogeneity in the immunologic phenotype, resulting in highly variable clinical courses, most likely due to the different effects of hypomorphic mutations. Treatment with antibiotics and IVIg is usually beneficial; hematopoietic stem cell transplantation may not be necessary, but can be effective. Features of hypohidrotic ectodermal dysplasia are generally not present, although some patients may have conical teeth or hypodontia (summary by Orange et al., 2004, Filipe-Santos et al., 2006, Salt et al., 2008, Heller et al., 2020).

Orange et al. (2004) reported a boy (patient 5) who developed sepsis with Haemophilus influenzae at 5 years of age after immunization, and later had a cutaneous mycobacterial infection. Medical history revealed possible earlier bacterial pneumonia. He responded to treatment for the mycobacterium without relapse. He did not have hypogammaglobulinemia, but did have decreased levels of some IgG subsets, and decreased NK cell cytotoxic activity compared to controls. The boy had no clinical evidence of ectodermal dysplasia. Orange et al. (2004) reported follow-up of this patient, who was described as a 15-year-old boy with a specific pattern of infectious susceptibility and immunodeficiency. He had pneumonia 4 times between the ages of 3 and 7 years and Haemophilus influenzae type b sepsis at age 5 years. He had a normal total IgG level, but IgG3 levels that were never greater than 10 mg/dL and no specific antibody against tetanus toxoid (despite receiving immunization) or H. influenzae polyribosyl phosphate; he was treated with immunoglobulin replacement. Laboratory studies showed variably impaired immunologic function, with reduced CD40-induced B-cell proliferation, variable Toll-like receptor-induced TNF production, and partially reduced NFKB nuclear translocation. He did not have ectodermal dysplasia and had normal dentition, hair pattern, and perspiration.

Niehues et al. (2004) reported a boy, born of healthy unrelated Polish parents living in Germany, with IMD33 without signs of ectodermal dysplasia. From the age of 15 months, he suffered from multiple episodes of disseminated Mycobacterium avium disease (affecting mostly lymph nodes and bones). At the age of 7 years, he was diagnosed with bronchiectasis caused by Haemophilus influenzae and Streptococcus pneumoniae. At the age of 11 years, the patient presented with extraintestinal disease caused by Salmonella enteritidis. At the age of 12, he developed severe autoimmune hemolytic anemia and died from herpes simplex virus 1 meningoencephalitis. Immunologic workup showed low IgA and IgG levels, with markedly high serum IgM levels and low levels of gamma-IFN. No serum antibodies against diphtheria toxoid and tetanus toxoid were detected, and titers of antibodies against H. influenzae were low despite complete routine vaccination. The patient also presented low serum titers of antibodies against S. pneumoniae and had no allohemagglutinin antibodies. Known molecular causes of hyper-IgM syndrome (308230) were excluded. The numbers of T, B, and NK lymphocytes and the proportions of the CD4+ and CD8+ T lymphocyte subsets were within normal ranges at the ages of 2 and 4 years, although he lacked memory B cells. Proliferative responses of T lymphocytes to mitogens were normal.

Ku et al. (2005) reported 2 unrelated boys with IMD33. They presented in the first years of life with recurrent severe systemic bacterial infections, including pneumococcus, H. influenzae, and Pseudomonas, as well as Candida. Immunoglobulin levels were normal, although IgM was low in 1 patient. Neither patient developed antibodies to pneumococcus, despite recurrent infections; patient 1 was unable to mount an antibody response to pneumococcal polysaccharide vaccination. However, both did respond to H. influenzae vaccine, and patient 2 mounted a response to tetanus toxoid. Neither patient had features of ectodermal dysplasia, although they had hypodontia and conical incisors. The mother of 1 patient had conical teeth, whereas the mother of the other patient had no clinical abnormalities. Heller et al. (2020) reported follow-up of one of the patients reported by Ku et al. (2005), noting that he was treated successfully with IVIg and lived an independent life at age 25.

Ku et al. (2007) described a 4.5-year-old boy, born to unrelated Belgian parents, with IMD33. He was noted to have hypodontia with conical incisors, but had only dry skin with normal sweating. He received all routine vaccinations with no adverse effect. At age 15 months, he was hospitalized for persistent fever with buccal cellulitis, caused by Streptococcus pneumoniae serotype 33. He recovered completely after intravenous cefuroxime for 7 days, but continued to have recurrent invasive infections with Streptococcus pneumoniae serotype 33. Beginning at age 23 months, he had serial vaccinations for pneumococcus, but again presented with recurrent invasive infections of Streptococcus pneumoniae serotype 23. Immunologic workup showed normal numbers of white cells and lymphocytes, normal Ig levels, and normal numbers of T, B, and NK cells. He had impaired antibody response to multiple vaccinations. Monthly prophylactic treatment with intravenous immunoglobulins was started when the patient was 3 years, 8 months old. Studies of patient fibroblasts showed impaired responses to stimulation by both IL1B and TNFA. This and other responses suggested a defect downstream of the TOLL/IL1R signaling pathway (see 603030).

Filipe-Santos et al. (2006) reported a multiplex American kindred (kindred A) in which 4 boys developed disseminated mycobacterial disease in an X-linked recessive pattern of inheritance. None of the patients had BCG vaccination, but all presented with disseminated M. avium infection between ages 5 and 14 years. Several developed other recurrent severe bacteremic infections with H. influenzae and Enterobacter. An unrelated boy of Italian/Serbian descent (kindred B) had BCG vaccination at age 2 months and presented with disseminated disease at age 2 years. At age 8 years, he was clinically well with no treatment. Another unrelated boy of German descent had recurrent infections in childhood, including bronchitis, pneumonitis, and H. influenzae, and presented at age 11 years with mycobacterial disease. In all patients, laboratory studies showed normal numbers of immune cells, normal T-cell proliferative responses, and normal immunoglobulins with proper antibody responses to vaccination, including pneumococcus, although this response was low and somewhat delayed. Detailed immunologic studies of all patients showed impaired CD40 signaling in monocytes and antigen-presenting cells, delayed nuclear accumulation of NFKB, and impaired secretion of IL12 by CD40L-expressing T cells. This resulted in impaired gamma-IFN production by T cells, ultimately resulting in increased susceptibility to mycobacterial infection. However, CD40-dependent proliferation and immunoglobulin class-switching of B cells was normal, and patients' blood and fibroblasts responded to other NFKB activators, such as TNFA, IL1B, and LPS. Some of the patients had sparse or conical teeth, which was long unrecognized, but no other features of ectodermal dysplasia.

Salt et al. (2008) reported a boy with recurrent infections, including Pneumocystis, CMV, and rotavirus. He had normal immunoglobulins and normal antibody response to diphtheria, tetanus, and H. influenzae B, but poor response to pneumococcal vaccination. Detailed immunologic studies showed impaired NK cell function and evidence of impaired T-cell receptor signaling through the NFKB pathway. Toll-like receptor function appeared to be normal. He had no evidence of ectodermal dysplasia.

Frans et al. (2017) reported a 2-year-old boy with IMD33. He presented at 1 year of age with otitis media and mastoiditis due to Pseudomonas infection, and later developed an EBV infection. Laboratory studies showed hypogammaglobulinemia, polysaccharide antibody deficiency, and low levels of switched memory B cells. Patient peripheral blood cells showed mildly impaired IL6 production in response to IL1B. He had no signs of ectodermal dysplasia. Treatment with immunoglobulin therapy resulted in clinical improvement.

Boisson et al. (2019) reported 2 brothers from a European family (family A) and a boy from a Japanese family (family B) with severe IMD33. The patients presented in infancy with severe systemic infections, including Klebsiella, respiratory syncytial virus, Enterobacter, E. coli, fungal infections, and HHV6. Although immunologic parameters were basically normal, 1 patient had no IgA and developed hypogammaglobulinemia with poor response to tetanus and H. influenzae vaccination. Two patients had other variable abnormalities, including low IgG levels, high white cells, transient neutropenia, lymphopenia, and low NK cell levels. TNFA production in response to LPS and IFNG was impaired in the 1 patient studied. None of the patients had features of ectodermal dysplasia; all died by 9 months of age. The mother in family A had mild features of IP.

Heller et al. (2020) reported a boy (patient 2) with IMD33 without ectodermal dysplasia. He had recurrent infections, including respiratory infections and oral HSV1. Immunoglobulin levels and tetanus antibodies were normal, but he had impaired response to polysaccharide vaccinations. He was successfully treated with IVIg.

Clinical Variability

Hsu et al. (2018) reported 4 adult males, including 2 sibs, who presented with disseminated mycobacterial infections between 26 and 38 years of age. All had a remote history of recurrent childhood infections, including H. influenzae. One patient had documented low IgM, increased IgA, and poor responses to pneumococcal, influenza, and measles vaccination. None had clear evidence of ectodermal dysplasia. Three of the patients died from the mycobacterial infection; the fourth patient was unable to clear the infection.

Most patients with IMD33 respond well to IVIg and prophylactic antibiotics (Frans et al., 2017, Heller et al., 2020).

Some patients with IMD33 have had successful bone marrow transplantation, although the outcomes are variable and a few may have persistent colitis. The absence of ectodermal dysplasia may be associated with a better outcome (Abbott et al., 2014).

The transmission pattern of IMD33 in the families reported by Filipe-Santos et al. (2006) was consistent with X-linked recessive inheritance.

In a 15-year-old boy with IMD33, Orange et al. (2004) identified a de novo hemizygous splice site mutation in the IKBKG gene (300248.0018), resulting in the skipping of exon 9 and the deletion of 19 residues, some of which affected the leucine zipper (LZ) domain. Analysis of patient peripheral blood and buccal epithelial cells showed presence of both mutant and wildtype transcripts. Western blot analysis using an antibody against the LZ domain showed barely detectable IKBKG protein levels in patient cells, whereas an antibody against the zinc finger domain showed normal protein levels. The presence of some normal transcripts may explain immunodeficiency without signs of ectodermal dysplasia in this patient. In vitro functional expression studies showed impaired, but not absent, nuclear translocation of NFKB in stimulated patient B cells compared to controls, as well as variable response to TNFA. Orange et al. (2004) postulated that exon 9 may be dispensable for ectodermal development.

In the boy with IMD33 reported by Niehues et al. (2004), Puel et al. (2006) found a hemizygous 1-bp insertion in exon 2 of the NEMO gene (300248.0019), resulting in premature termination. Puel et al. (2006) showed that a Kozakian methionine codon located immediately downstream from the insertion allowed the reinitiation of translation. The findings suggested that residual production of an NH2-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages, but was insufficient for the development of protective immune responses.

In 2 unrelated boys with IMD33, Ku et al. (2005) identified hemizygous mutations in the IKBKG gene (c.811_828del, 300248.0025 and L80P, 300248.0026). The mutations occurred in the coiled-coil domains of the protein. Western blot analysis of patient cells showed presence of the IKBKG protein, but fibroblasts had poor IL6 production in response to TNFA and IL1B compared to controls. The findings were consistent with a hypomorphic allele. The patients had hypodontia and conical teeth, but no other features of ectodermal dysplasia. One carrier mother also had conical teeth.

In affected males from 3 unrelated kindreds with IMD33, Filipe-Santos et al. (2006) identified 2 hemizygous missense mutations in the NEMO gene (E315A, 300248.0021 and R319Q, 300248.0022), both of which occurred in the LZ domain and were predicted to disrupt a salt bridge. Western blot and flow cytometric analyses showed normal expression of the mutant NEMO proteins. Patient mononuclear cells responded normally to most stimuli, but IFNG (147570) and IL12 (see 161561) production in response to PHA mitogen was impaired due to defective CD40 (109535) signaling in monocytes and dendritic cells. Filipe-Santos et al. (2006) concluded that mutations in NEMO that disrupt the leucine zipper domain provide a genetic etiology to X-linked recessive immunodeficiency with a particular susceptibility to mycobacterial disease.

In a Belgian boy with IMD33, Ku et al. (2007) identified a hemizygous mutation in the IKBKG gene (R173G; 300248.0023) that resulted in abnormal splicing. Western blot analysis showed decreased levels of the protein compared to controls, consistent with partial IKBKG deficiency. The mother was heterozygous for this mutation.

In a 2-year-old boy with IMD33, Frans et al. (2017) identified a hemizygous missense mutation in the IKBKG gene (E57K; 300248.0029). The mutation affected the N-terminal domain of the protein. His mother, who also carried the mutation, had a history of recurrent sinorespiratory infections, but no signs of IP. The variant was present at a low frequency (0.001) in the ExAC database. Patient peripheral blood cells showed mildly decreased IL6 production after stimulation with IL1B compared to controls. However, NEMO expression in patient fibroblasts was normal, and IKBA was degraded normally upon stimulation with IL1B or TNFA, suggesting a specific effect of the mutation. In vitro functional expression studies in IKBKG-null cells transfected with the mutation showed mildly impaired IL6 production after stimulation with TNFA or IL1B compared to controls. Frans et al. (2017) noted that mutations affecting the N terminus of NEMO tend to lead to decreased production of immunoglobulins; the authors postulated a hypomorphic effect of this variant.

In 4 adult males from 3 unrelated families with IMD33 manifest as disseminated mycobacterial infections, Hsu et al. (2018) identified hemizygous splice site mutations in the 5-prime untranslated region of the IKBKG gene. Three patients from 2 families (families A and B) carried a c.1-16G-C transversion (300248.0030) at the last base of the first untranslated exon. The patient from family C carried a hemizygous c.1-16+G-T in the adjacent intron. Analysis of cells from the patient with the c.1-16G-C mutation showed a splicing abnormality, resulting in a 110-bp deletion at the 3-prime end of exon 1. This molecular defect resulted in decreased transcript and protein levels compared to controls (about 30%). Cells derived from the patients in families A and B failed to upregulate cytokines in response to certain TLR agonists, suggesting that this IKBKG mutation is hypomorphic.

In 3 boys from 2 families of European and Japanese descent who died from IMD33, Boisson et al. (2019) identified a deep intronic mutation (IVS4+866C-T; 300248.0024) in the IKBKG gene that created a new splicing donor site and resulted in a 44-nucleotide pseudoexon that produced a frameshift. The boy in the European family inherited the mutation from his mother, who had mild incontinentia pigmenti. The mutation in the Japanese boy occurred de novo. The variant was not found in the 1000 Genomes Project or gnomAD databases. In vitro studies showed impaired, but not abolished NFKB activation. Aberrant splicing rates differed between cell types, with wildtype NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell-derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells.

In a boy (patient 1) with IMD33, Abbott et al. (2014) identified a hemizygous missense mutation in the first coiled-coil domain of the NEMO gene (D113N; 300248.0032). The patient had previously been reported in detail by Salt et al. (2008); his unaffected mother also carried the mutation.

Heller et al. (2020) identified a hemizygous D113N mutation in a boy with IMD33. His mother and grandmother, who were presumably unaffected, carried the heterozygous mutation. However, the proband's 40-year-old male cousin, who did not have recurrent infections and had normal response to polysaccharide antibodies, was hemizygous for D113N. Heller et al. (2020) noted that the allele frequency for this variant is rather high (0.009572), and that some suggest it may be a polymorphism (see Fusco et al., 2004).

In general, patients with NKBKG mutations affecting the C-terminal zinc finger domain have a more severe clinical course with ectodermal dysplasia, whereas patients with mutations affecting the leucine zipper domain or the more N-terminal coiled-coil domains have a less severe clinical course and usually do not show features of ectodermal dysplasia, although isolated hypodontia and/or conical teeth may be present (Orange et al., 2004, Heller et al., 2020).