Alternative titles; symbols
SNOMEDCT: 703525006; ORPHA: 238468, 69088, 98813; DO: 0081078;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Ectodermal dysplasia and immunodeficiency 1 | 300291 | X-linked recessive | 3 | IKBKG | 300248 |
A number sign (#) is used with this entry because of evidence that ectodermal dysplasia and immunodeficiency-1 (EDAID1) is caused by hemizygous mutation in the IKK-gamma gene (IKBKG, or NEMO; 300248) on chromosome Xq28.
Hemizygous mutation in the IKBKG gene also causes X-linked recessive immunodeficiency-33 (IMD33; 300636) in males. Heterozygous mutation in the IKBKG gene causes X-linked dominant incontinentia pigmenti (IP; 308300) in females.
Ectodermal dysplasia with immunodeficiency-1 (EDAID1) is an X-linked recessive disorder that characteristically affects only males. Affected individuals have onset of recurrent severe infections due to immunodeficiency in early infancy or in the first years of life. There is increased susceptibility to bacterial, pneumococcal, mycobacterial, and fungal infections. Laboratory studies usually show dysgammaglobulinemia with low IgG subsets and normal or increased IgA and IgM, consistent with impaired 'class-switching' of B cells, although immunologic abnormalities may be subtle compared to the clinical picture, and B- and T-cell numbers are usually normal. There is a poor antibody response to polysaccharide vaccinations, particularly pneumococcus; response to other vaccinations is variable. Patients also have features of ectodermal dysplasia, including conical incisors, hypo/anhidrosis, and thin skin or hair. Severely affected individuals may also show lymphedema, osteopetrosis, and, rarely, hematologic abnormalities. The phenotype is highly variable, likely due to different hypomorphic mutations, and may be fatal in childhood. Intravenous immunoglobulins and prophylactic antibiotics are used as treatment; some patients may benefit from bone marrow transplantation. Although only males tend to be affected with immunodeficiency, many patients inherit a mutation from a mother who has mild features of IP or conical teeth (summary by Doffinger et al., 2001, Orange et al., 2004, Roberts et al., 2010, Heller et al., 2020).
Genetic Heterogeneity of Ectodermal Dysplasia and Immune Deficiency
Also see EDAID2 (612132), caused by mutation in the NFKBIA gene (164008).
Zonana et al. (2000) studied males from 4 families with hypohidrotic ectodermal dysplasia and immunodeficiency segregating as an X-linked recessive trait. The patients presented in the first years of life with recurrent infections, including pneumonia, bacterial infections of the bone and soft tissue, and sepsis. Organisms included pneumococcus, Pseudomonas, pneumocystis, and atypical mycobacteria. Laboratory studies showed dysgammaglobulinemia with increased IgM and low levels of IgA and IgG, although this was somewhat variable. Other immunologic parameters were essentially normal, although there was no antibody response to pneumococcal infection or vaccination. Response to tetanus was normal in some patients. The patients also had features of ectodermal dysplasia, including conical teeth, abnormal teeth, inability to sweat or poor sweating, and sometimes sparse hair. Two brothers in family 4 had the most severe clinical course, with death occurring by 3 years of age. These boys also had osteopetrosis, thus expanding the phenotype. Despite treatment, usually with IVIg, all had significant morbidity and mortality from recurrent infections. The mothers had variable mild manifestations, ranging from normal dentition to mild hypodontia or conical teeth; 2 had some skin hyperpigmentation. One mother (family 2) had low IgA, but no immune dysfunction.
Doffinger et al. (2001) identified 7 boys from 5 unrelated families with EDAID1. Four patients died between 9 months and 17 years of age. In all patients, ectodermal dysplasia features were somewhat milder compared to other forms of anhidrotic ectodermal dysplasia. Most children experienced failure to thrive, recurrent digestive tract infections, often with intractable diarrhea and recurrent ulcerations, recurrent respiratory tract infections, often with bronchiectasis, and recurrent skin infections, suggesting that they were generally susceptible to various gram-positive and gram-negative bacteria. The only blood immunologic abnormality detected in all patients tested was a poor antibody response to polysaccharide antigens (anti-AB isohemagglutinins and antibodies against H. influenzae and S. pneumoniae). In most patients, low levels of IgG or IgG2 were detected. Intravenous immunoglobulins and prophylactic antibiotics had occasionally been sufficient to improve clinical status when started early.
Jain et al. (2001) reported 2 unrelated male patients with EDAID1 associated with increased IgM and decreased IgG. One patient presented with pneumococcal meningitis at 9 months of age, and both patients had frequent upper respiratory and sinus infections despite intravenous gamma-globulin replacement therapy. Neither patient had a history of opportunistic infections suggestive of T-cell dysfunction. One patient had conical-shaped molars and incisors, but skin biopsies for both patients confirmed the absence of eccrine sweat glands and a paucity of hair follicles, consistent with ectodermal dysplasia. Both had normal bone density and did not have Mycobacterium avium complex infection.
Orange et al. (2002) reported 3 unrelated boys with EDAID1. Patient 1 was a 2-year-old boy who presented with severe systemic infections, including Listeria sepsis, Streptococcus bovis meningitis, and recurrent CMV sepsis and colitis. Laboratory studies showed increased IgM, variably decreased IgG, and detectable diphtheria and tetanus titers. Patients 2 and 3 were teenagers with a history of recurrent infections since childhood, including sinusitis, pneumonia, oral herpetic lesions, and systemic invasive atypical Mycobacterium infections. They had normal, decreased, or increased IgG and IgA, but normal IgM, as well as decreased specific antibody levels. Both were treated with IVIg. Detailed immunologic studies showed that all patients had defective CD40 (109535) signaling with impaired B-cell proliferative responses and decreased activation of NFKB compared to controls. NK cell levels were normal, but there was deficient NK cell cytotoxicity that could be partially overcome in vitro and in vivo with IL2 (161560) treatment.
Johnston et al. (2016) reported a male infant who presented with systemic Staphylococcus aureus infection associated with multiple brain infarcts, microabscesses, and white matter abnormalities. He was noted to have features of ectodermal dysplasia, such as sparse hair and absent eyelashes and eyebrows. He also had edema of the scalp, hands, scrotum, and lower extremities. Laboratory studies showed dysgammaglobulinemia with mostly low Ig levels, whereas T, B, and NK cells were normal. The infection persisted despite treatment, and he died at 18 days of age. The patient's mother and several female relatives had features consistent with IP; X-inactivation studies on the mother showed nonrandom X-chromosome inactivation with expression of the wildtype allele. Patient peripheral blood cells showed impaired cytokine production in response to stimulation of Toll-like receptors compared to controls.
Heller et al. (2020) reported a boy (patient 1) with severe EDAID1. He presented in infancy with a septic Enterobacter and Pneumocystis infection associated with decreased IgG and IgM. He also had lymphedema of the lower leg. Detailed immunologic studies showed functional B- and T-cell deficiency with impaired class-switched memory B cells, impaired CD3-induced T-cell proliferation, and skewing toward naive cells, indicating a defect in adaptive immunity. There was also impaired NFKB signaling through the Toll-like receptor, IL1B, and TNFA pathways, indicating defects in innate immunity. The patient underwent hematopoietic stem cell transplantation, but developed complications, including persistent colitis. Heller et al. (2020) concluded that T-cell dysfunction in EDAID1 predicts a severe clinical course.
Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema
The International Incontinentia Pigmenti Consortium (2000) reported a male infant (patient IP85) with a severe form of EDAID1. In addition to recurrent infections, the boy had osteopetrosis and lymphedema. He was born with multiple capillary hemangiomas, developed lymphedema of the lower limbs, and had failure to thrive. Despite a destructive red blood cell picture and recurrent infections due to poor immune function, he survived 2 and a half years, but eventually succumbed to a tuberculosis infection. He had had operations to remove his spleen and an intestinal stricture, and biopsies revealed abnormal capillary beds in the gut, extrahepatic erythropoiesis, and osteopetrosis. His skin developed a reticular pigmentation. Cognitive development was normal. Genetic analysis identified a hemizygous X420W mutation in the IKBKG gene (300248.0002) that was inherited from his mother, who had IP. Mansour et al. (2001) presented more details of this patient (IP85), who also had hematologic disturbances, such as hemolytic anemia and thrombocytopenia. Doffinger et al. (2001) also studied this patient and classified him as having 'anhidrotic ectodermal dysplasia with immunodeficiency, osteopetrosis, and lymphedema' (OLEDAID), which is within the phenotypic spectrum of EDAID1.
Doffinger et al. (2001) reported another boy, of French descent, with a similar OLEDAID phenotype, including recurrent infections, anhidrotic ectodermal dysplasia, lymphedema, and osteopetrosis. Blood monocytes and polymorphonuclear cells were normal in number and morphology, and B- and T-cell counts and responses to vaccine protein antigens (tetanus and polio) were normal. However, serum titers of antibodies against pneumococcus were low, despite proven infection. Serum levels of immunoglobulin isotypes were normal for age, with the exception of low to normal IgG levels. This patient and the patient described by Mansour et al. (2001) both died in the first years of life from overwhelming infectious disease caused by a variety of microorganisms, including gram-positive cocci, gram-negative bacilli, mycobacteria, and fungi. The French boy carried a hemizygous X420W mutation in the IKBKG gene that was inherited from his mother, who had mild IP. In vitro functional expression studies showed that the X420W mutation resulted in a 50 to 60% reduction of NF-kappa-B activation. Patient cells showed impaired cellular responses to TNF-alpha (191160) and a lower level of IFN-gamma (147570) production upon costimulation with IL12 (see 161560), IL1-beta (147720), or IL18 (600953) compared to controls. There was also evidence of impaired cellular responses to lipopolysaccharide (LPS) and dissociated cellular responses to CD154 (CD40LG; 300386), suggesting that some but not all CD40 (109535)-mediated signals are NEMO-dependent in both dendritic cells and B cells. The findings indicated that the X420W mutation impairs but does not abolish NFKB activation, consistent with a hypomorphic allele and postnatal survival of the boys. Dupuis-Girod et al. (2002) reported that the French patient described by Doffinger et al. (2001) underwent hematopoietic stem cell transplantation, but developed complications and died at 18 months of age.
Roberts et al. (2010) reported a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema. He presented in the neonatal period with recurrent skin pustules, followed by conjunctivitis and Enterobacter septicemia associated with seizures. He later developed additional infections, including septic arthritis, gastroenteritis, and otitis media. Laboratory studies showed increased IgM, normal IgA, and fluctuating low IgG. He developed recurrent infections with group B Streptococcus, salmonella, and Molluscum contagiosum. Ectodermal dysplasia findings included conical teeth, frontal bossing, and absence of sweat glands. At around 18 months, he developed lymphedema of the hands, feet, and genitalia, as well as mild osteopetrosis on imaging. Other features included skin abnormalities, cortical ischemia, asthma, and hypothyroidism. Treatment was mostly effective and he had subsequent normal development with the ability to attend school. Genetic analysis identified a hemizygous 2-bp deletion (300248.0027) in the IKBKG gene. His mother, who had IP, carried the mutation in heterozygous state.
Female Patient with Transient Immunodeficiency
Martinez-Pomar et al. (2005) reported a female infant who presented at birth with classic features of IP. In the first months of life, she developed recurrent infections associated with high IgM and low IgG. She was treated successfully with IVIg, and the immunodeficiency spontaneously resolved. Genetic analysis identified a heterozygous frameshift mutation in the IKBKG gene (300248.0017). In vitro studies showed impaired IKBA degradation and defective activation of the NFKB pathway compared to controls. The X-inactivation status of peripheral blood cells from the patient was evaluated at 24, 30, 38, and 48 months of age and was found to have progressed from random at 24 and 30 months to skewed at 38 and 48 months of age, at which point her immunodeficiency had disappeared. Martinez-Pomar et al. (2005) stated that this was the first time that selection against the mutated X chromosome in X-linked disease had been documented in vivo.
Clinical management of EDAID1 depends on the severity of the disorder. Many patients respond well to IVIg and prophylactic antibiotics (summary by Orange et al., 2004, Heller et al., 2020).
Some patients with EDAID1 have had successful bone marrow transplantation, although the outcomes are variable and a few may have persistent colitis (Abbott et al., 2014).
In a boy with EDAID1 (patient 1) who had recurrent CMV infection associated with impaired NK cytotoxic function, Orange et al. (2002) found that in vivo and in vitro treatment with IL2 enhanced NK cell cytotoxicity. The findings suggested that IKBKG is also important for NK cell cytotoxicity and that IL2 may benefit patients with these defects. Pai et al. (2008) reported follow-up of this boy. He underwent allogeneic bone marrow transplant from an unaffected sister, which resulted in correction of several immunologic abnormalities, including restoration of cytokine production in response to TLR agonists and LPS, increased CD40-mediated B-cell proliferation, and enhanced NK cell toxicity. Unfortunately, the patient continued to have flare-ups of colitis, often associated with bacterial infections.
The transmission pattern of EDAID1 in the families reported by Zonana et al. (2000) was consistent with X-linked recessive inheritance.
In affected males from 4 unrelated families with EDAID1, Zonana et al. (2000) identified hemizygous mutations in the IKBKG gene (300248.0007-300248.0010). All mutations occurred in exon 10 of the gene, which encodes the C-terminal zinc finger domain, and were thus predicted to result in a loss of NFKB activation. Since mutations in this gene cause IP in females and are usually lethal in males, Zonana et al. (2000) hypothesized that the mutations identified in males with EDAID1 are hypomorphic; functional studies of the variants were not performed.
In 2 unrelated male patients with EDAID1, Jain et al. (2001) identified hemizygous missense mutations in the NEMO gene. Both mutations (C417R, 300248.0009 and D406V, 300248.0011) occurred in the putative zinc finger domain of the protein. Detailed functional studies showed impaired CD40L-mediated degradation of IKBA (164008), impaired CD40L-induced class switching in patient B cells, and impaired secretion of IL12 and TNF in response to stimulation with CD40L. However, there was some cytokine response to LPS, suggesting residual innate immunity. Jain et al. (2001) concluded that NEMO has a regulatory function in NFKB activation and B-cell Ig class switching.
In 3 unrelated boys with EDAID1, Orange et al. (2002) identified hemizygous mutations in the IKBKG gene. Two mutations occurred in the zinc finger domain (C417R, 300248.0009 and Q403X, 300248.0015), and 1 occurred in the first coiled-coil domain (L153R; 300248.0014).
In affected members and obligate carriers of a family with ectodermal dysplasia and immunodeficiency, originally reported by Lie et al. (1978), Orstavik et al. (2006) identified a splice site mutation in the IKBKG gene (300248.0016). The family had 3 stillborn males, 3 affected males who were small for gestational age and died within 8 months, and 1 male who died at age 5 years. The 5-year-old had cone-shaped teeth, oligodontia, serious bacterial infections, and inflammatory bowel disease. Isolated subtle tooth anomalies were found in 3 carriers examined, of whom 2 had random X inactivation and 1 had extreme skewing. Orstavik et al. (2006) stated that this was the first report of random X inactivation in carriers of EDAID.
In a boy with EDAID1, Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT; 300248.0027) in the IKBKG gene predicted to result in a frameshift and premature termination. His mother, who carried the mutation in heterozygous state, showed signs of IP since childhood. Functional studies of the variant were not performed.
In a male infant with lethal EDAID1, Johnston et al. (2016) identified a hemizygous splice site mutation in the IKBKG gene (300248.0028). Western blot analysis of patient cells showed reduced size of the IKBKG protein, consistent with a frameshift and premature termination.
In a boy (patient 1) with EDAID1, Heller et al. (2020) identified a hemizygous splice site mutation in the IKBKG gene (300248.0031), resulting in a frameshift and premature termination, with loss of the zinc finger domain. Patient cells showed decreased IKBKG levels compared to controls; in vitro studies showed impaired degradation of IKBA and impaired IL6 production upon stimulation with IL1B and TNFA. His mother and sister, who were heterozygous for the mutation, had incontinentia pigmenti (IP; 308300).
Anhidrotic Ectodermal Dysplasia with Immunodeficiency, Osteopetrosis, and Lymphedema
In 2 unrelated male patients with OLEDAID syndrome, Doffinger et al. (2001) identified an X420W mutation in the IKBKG gene (300248.0002). Different alleles were present at the flanking polymorphic loci in the 2 patients, indicating 2 independent mutation events.
In a 6-year-old boy with hypohidrotic ectodermal dysplasia, immunodeficiency, osteopetrosis, and lymphedema, Roberts et al. (2010) identified a hemizygous 2-bp deletion (c.1182_1183delTT; 300248.0027) in the IKBKG gene. His mother, who had IP since childhood, carried the mutation in heterozygous state. The mutation was predicted to result in a frameshift and premature termination, but studies of patient cells were not performed.
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 do not show features of ectodermal dysplasia, although isolated hypotonia and/or conical teeth may be present (Orange et al., 2004, Heller et al., 2020).
By studying responses to the TLR4 (603030) ligand LPS and to the bacterial chemoattractant fMLP in polymorphonuclear neutrophils (PMNs) from 1 patient with IRAK4 deficiency (607676) and 3 patients with NEMO deficiency causing immunodeficiency with ectodermal dysplasia, Singh et al. (2009) demonstrated reduced or absent superoxide production after impaired priming and activation of the oligomeric neutrophil NADPH oxidase (NOX; see 300481). The response was particularly weak or absent in IRAK4-deficient PMNs. NEMO-deficient PMNs had a phenotype intermediate between IRAK4-deficient PMNs and normal PMNs. Decreased LPS- and fMLP-induced phosphorylation of p38 (MAPK14; 600289) was observed in both deficiencies. Singh et al. (2009) proposed that decreased activation of NOX may contribute to increased risk of infection in patients with IRAK4 deficiency or NEMO deficiency.
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