Alternative titles; symbols
Other entities represented in this entry:
ORPHA: 70592;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q12 | Immunodeficiency 67 | 607676 | Autosomal recessive | 3 | IRAK4 | 606883 |
A number sign (#) is used with this entry because of evidence that immunodeficiency-67 (IMD67) is caused by homozygous or compound heterozygous mutation in the gene encoding interleukin-1 receptor-associated kinase-4 (IRAK4; 606883) on chromosome 12q12.
Immunodeficiency-67 (IMD67) is an autosomal recessive primary immunodeficiency characterized by recurrent severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae and Staphylococcus aureus; Pseudomonas and atypical Mycobacteria may also be observed. IMD67 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis representing up to 41% of the bacterial infections. The mortality rate in early childhood is high, with most deaths occurring before 8 years of age. Affected individuals have an impaired inflammatory response to infection, including lack of fever and neutropenia, although erythrocyte sedimentation rate (ESR) and C-reactive protein may be elevated. General immunologic workup tends to be normal, with normal levels of B cells, T cells, and NK cells. However, more detailed studies indicate impaired cytokine response to lipopolysaccharide (LPS) and IL1B (147720) stimulation; response to TNFA (191160) is usually normal. Patients have good antibody responses to most vaccinations, with the notable exception of pneumococcal vaccination. Viral, fungal, and parasitic infections are not generally observed. Early detection is critical in early childhood because prophylactic treatment with IVIg or certain antibiotics is effective; the disorder tends to improve naturally around adolescence. At the molecular level, the disorder results from impaired function of selective Toll receptor (see TLR4, 603030)/IL1R (see IL1R1, 147810) signaling pathways that ultimately activate NFKB (164011) to produce cytokines (summary by Ku et al., 2007; Picard et al., 2010; Grazioli et al., 2016).
See also IMD68 (612260), caused by mutation in the MYD88 gene (602170), which shows a similar phenotype to IMD67. As the MYD88 and IRAK4 genes interact in the same intracellular signaling pathway, the clinical and cellular features are almost indistinguishable (summary by Picard et al., 2010).
Kuhns et al. (1997) reported a 15-year-old girl with a history of recurrent infections since early childhood. She did not have delayed separation of the umbilical cord at birth. Her infections, which were associated with minimal or no febrile response and persistent neutropenia, included pneumococcal meningitis, Neisseria, and Staphylococcus aureus, as well as other infections. She had poor response to LPS and IL1B, but normal response to TNFA, in vivo and in vitro, suggesting a defect in an upstream signaling pathway. In a follow-up report of this patient, Medvedev et al. (2003) noted that her clinical manifestations improved after adolescence.
Haraguchi et al. (1998) described a 3-year-old girl, born of an incestuous relationship, who presented in infancy with recurrent severe infections, including cellulitis, lymphadenitis, septic arthritis, and sepsis due to Staphylococcus aureus and pneumococcus. She did not have fever. Detailed immunologic workup showed deficient production of IL12 (see IL12B, 161561). The patient's peripheral blood mononuclear cells (PBMCs) exhibited normal proliferative responses to antigens and normal immune responses, including in vivo production of antibodies to diphtheria, tetanus, and pneumococcal antigens. Immunoglobulin levels and B-cell and T-cell phenotypes were also normal. In contrast, IL12 p70 heterodimer production was undetectable by using supernatants of the patient's stimulated PBMCs when compared with control cells treated similarly. Although present, IFNG (147570) was reduced, and patient cells did not produce IL12 in response to recombinant IFNG, Staphylococcus aureus, or LPS. Patient cells were able to produce IL2 (147680), IL6 (147620), TNFA (191160), and IFNG after appropriate stimulation. The findings suggested either a defect in the signaling pathways for the activation of IL12B gene expression or an abnormality in IL12B itself.
Picard et al. (2003) described 3 unrelated children, including the child originally reported by Haraguchi et al. (1998), with recurrent infections and poor inflammatory response in whom extracellular, pyogenic bacteria were the only microorganisms responsible for infection. Gram-positive Streptococcus pneumoniae and Staphylococcus aureus were the most frequently found and were the only pathogens identified in 2 patients. Infections began early in life but became less frequent with age, and the patients were well with no treatment at ages 6, 11, and 7 years. All known primary immunodeficiencies were excluded. In particular, the patients had normal serum antibody titers against protein and polysaccharide antigens, including those from S. pneumoniae. None of the patients' monocytes responded to LPS; however, they responded normally to TNF-alpha (191160). The patients did not respond to IL1B, IL18 (600953), or any of the TLR1-6 (see 601194) or TLR9 (605474) ligands, as assessed by activation of NF-kappa-B (see 164011) and p38-MAPK (600289) and induction of IL1B IL6, IL12, TNFA, and IFNG.
In a follow-up of the patients reported by Picard et al. (2003), Day et al. (2004) found that 2 continued to do well, but 1, an 8-year-old girl, was unable to sustain antibody responses to polysaccharide or protein antigens or to a neoantigen-bacteriophage. She continued to have recurring bacterial and fungal infections, eventually requiring intravenous immunoglobulin therapy. They recommended testing for IRAK4 deficiency in patients with recurrent bacterial and fungal infections without sustained antibody response to immunization.
Enders et al. (2004) reported 2 sibs, born of consanguineous Turkish parents, with IMD67. They presented in infancy with recurrent infections, including bronchitis, gastroenteritis, osteomyelitis, and pneumococcal meningitis. Despite treatment, both died, at 14 and 2 months of age. During the infections, both children had a poor inflammatory response without fever, suggesting a deficiency in NFKB-mediated immunity.
Takada et al. (2006) reported 2 Japanese sibs with IMD67. Both had delayed separation of the umbilical cord at 34 to 39 days after birth. The older sib presented in the first years of life with recurrent pneumococcal meningitis and arthritis, which was fatal at age 2. Basic immunologic studies were unremarkable, and he had received several vaccinations without adverse effect; he did not receive pneumococcal vaccination. The younger brother had no apparent infection at 5 months of age. However, in vitro studies showed that patient mononuclear cells had defective IL6 and TNFA production in response to LPS and IL1B. Flow cytometric studies showed impaired intracellular TNFA production in response to LPS, which the authors suggested could be used as a screening method. Takada et al. (2016) reported follow-up of this family, noting that the younger brother from the first report and another affected brother, both of whom had the disorder, had not had invasive bacterial infections due to antimicrobial prophylaxis since early infancy after the diagnosis.
Ku et al. (2007) reported a 7-year-old boy, born to unrelated Hungarian parents, with IMD67. He had routine immunizations with no complications. At age 3 years, he presented with arthritis of the right hip due to pneumococcal infection, followed by pneumococcal meningitis at age 5. During these episodes, he had either no fever or a low-grade fever and low white blood cell counts, indicating a poor inflammatory response. ESR and C-reactive protein were increased. Immunologic workup was essentially normal, although he failed to mount a good antibody response to pneumococcal vaccination; responses to other vaccinations were normal. He had no other bacterial, fungal, or viral infections. Patient cells showed impaired IL6 production in response to IL1B and LPS compared to controls, although response to TNFA was normal. These findings suggested a defect in the TLR (see 603030)-NFKB (see 164011) signaling pathway.
Lavine et al. (2007) reported 3 sibs with IMD67. The first child died at age 5 months due to septic shock associated with Staphylococcus aureus meningitis. The other 2 sibs, who were twins, had recurrent severe systemic infections since early childhood, mainly due to pneumococcus, but also Pseudomonas and atypical Mycobacterium. Both twins had delayed or attenuated signs of inflammation, such as absence of fever and persistent neutropenia. They were treated with IVIg until about age 18 years, but did not have recurrence of the infections as young adults. Immunologic studies showed impaired IL6 production in response to LPS or IL1B compared to controls. There was also some evidence of T-cell dysfunction, including low numbers of CD3+ T cells and variably impaired proliferative responses to antigens. There was a normal antibody response to most vaccinations, but not to pneumococcal vaccine. These findings indicated defects in both the adaptive and innate immune systems, and also suggested that the condition may improve with age.
Ku et al. (2007) reported 28 patients with IMD67. Many of the patients had previously been reported. Most patients developed invasive and often recurrent pneumococcal disease in childhood, but other infections, except for severe Staphylococcal disease, were rare. Although nearly half of the patients died, death occurred only in patients 8 years old and younger. Older patients tended to have remission of the disease. Detailed analysis of patient leukocyte subsets showed that only the TLR3 agonist poly(I:C) could induce production of 11 non-IFN cytokines. The TLR4 agonist, LPS, could induce some responses in myeloid dendritic cells and monocyte-derived dendritic cells. The TLR3 (603029)- and TLR4-interferon-alpha (IFNA; 147660)/beta (IFNB; 147640) pathways were not impaired. Ku et al. (2007) concluded that IRAK4-dependent TLRs and IL1Rs are vital for childhood immunity to pyogenic bacteria, particularly S. pneumoniae, but they are not essential for protective immunity to most infections.
Hoarau et al. (2007) reported a 14-year-old French boy, born of unrelated patients, with IRAK4 deficiency characterized by recurrent infections, osteomyelitis, and cellulitis beginning at age 15 days. Apart from elevated C-reactive protein (CRP; 123260) and very low neutrophil numbers, his immunologic status was normal.
Picard et al. (2010) reported and reviewed the features of 48 patients from 31 kindreds with IMD67, including 36 previously reported patients and 12 new patients. The families originated from several countries; 5 families were consanguineous. In general, immunologic investigations showed normal T and B lymphocytes, NK cells, monocytes, dendritic cells, and Ig levels, although some patients had relatively high levels of certain Ig subsets. These patients had good antibody responses to most vaccinations, although about half had poor response to pneumococcal antigen. Most patients developed early-onset invasive bacterial infections, including meningitis, sepsis, arthritis, osteomyelitis, and deep tissue abscesses. Noninvasive cutaneous or upper respiratory infections were also observed. The most common organisms were Streptococcal pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Less common organisms included H. influenzae, Shigella, and Neisseria. Affected individuals had an impaired inflammatory response, manifest as poor or absent fever and low leukocyte and neutrophil levels; C-reactive protein levels were variable. Functional studies of patient cells show impaired cytokine responses to TLR and IL1R agonists, with, for example, low IL6 and low TNFA production. Many died of the disease, all before 8 years of age, and most before 2 years. Prophylactic treatment with antibiotics and IVIg was beneficial for survival. Clinical status and outcome improved with age, particularly around adolescence. Picard et al. (2010) noted the narrow susceptibility to certain bacterial infections and emphasized that early diagnosis is critical to initiate treatment.
Grazioli et al. (2016) reported 2 sisters, born of unrelated European Canadian parents, with IMD67 manifest as severe invasive pneumococcal meningitis resulting in death at 2 and 3 years of age. They both had routine immunizations early in life, normal immune cell levels, and no fever during the infections, indicating poor inflammatory responses.
Takada et al. (2016) reported 10 Japanese patients from 6 unrelated families with IMD67. One of the families had previously been reported (Takada et al., 2006); the sibs in that family were treated early and did not have invasive infections. The other 8 patients had severe invasive bacterial infections before the age of 4 years. Seven of them had pneumococcal meningitis, and 5 died of the infection despite early intervention with antibiotic therapy. Four patients had delayed separation of the umbilical cord (later than 21 days). Laboratory studies showed no apparent abnormalities in serum Ig levels, lymphocyte subsets, NK activity, or lymphocyte proliferative response against PHA. However, the patients studied had decreased TNFA production from stimulated monocytes.
The transmission pattern of IMD67 in the families reported by Picard et al. (2003) was consistent with autosomal recessive inheritance.
In 3 patients with IMD67, Picard et al. (2003) identified homozygous loss-of-function mutations in the IRAK4 gene (see 606883.0001-606883.0002). In each case, the mutations were associated with complete deficiency for the kinase. One of the patients was originally reported by Haraguchi et al. (1998).
In a 15-year-old girl with IMD67 (Kuhns et al., 1997), Medvedev et al. (2003) identified compound heterozygous mutations in the IRAK4 gene (606883.0002 and 606883.0003). Both mutations resulted in proteins with intact death domains but truncated kinase domains, precluding expression of full-length IRAK4 and conferring a recessive phenotype.
In a patient, born of consanguineous Turkish parents, with IMD67, Enders et al. (2004) identified a homozygous frameshift mutation (c.573delA; 606883.0008) in the IRAK4 gene. No material was available for further analysis, but the mutation segregated with the disorder in the family. A similarly affected sib had died of the disease, but no DNA from this sib was available.
In 2 Japanese sibs with IMD67, Takada et al. (2006) identified a homozygous frameshift mutation in the IRAK4 gene (606883.0009). The mutation segregated with the disorder in the family.
In a 7-year-old boy born of unrelated Hungarian parents, Ku et al. (2007) found that IMD67 was related to compound heterozygosity for 2 mutations in the IRAK4 gene, located in intron 10 (c.1189-1G-T, 606883.0004 and c.1188+520A-G, 606883.0005). The authors noted that this patient was the first in whom noncoding mutations in the IRAK4 gene had been found.
In 2 sibs with IMD67, Lavine et al. (2007) identified a homozygous nonsense mutation in the IRAK4 gene (Q293X; 606883.0002). The mutation segregated with the disorder in the family.
In a 14-year-old French boy with IMD67, Hoarau et al. (2007) identified compound heterozygous mutations in the IRAK4 gene (see 606883.0006 and 606883.0007). Stimulation of the patient's PMNs with TLR agonists revealed the absence of IRAK1 (300283) phosphorylation and impaired PMN responses. However, responses to the TLR9 agonist CpG were normal, except for cytokine production. Impairment of TLR9 responses was observed after pretreatment with PI3K (see 601232) inhibitors. Hoarau et al. (2007) proposed that there may be an alternative TLR9 pathway leading to PI3K activation independently of the classical MYD88 (602170)-IRAK4 pathway. They suggested that this alternative pathway may play a role in control of infections by microorganisms other than pyogenic bacteria in patients with IRAK4 deficiency.
In 9 patients from 5 unrelated Japanese families with IMD67, Takada et al. (2016) identified a homozygous frameshift mutation in the IRAK4 gene (606883.0009). Another affected Japanese patient (patient 4) was compound heterozygous for that mutation and a nonsense mutation. The findings suggested that the frameshift mutation is a founder mutation in the Japanese population.
By studying responses to the TLR4 ligand, LPS, and to the bacterial chemoattractant, fMLP, in PMNs from 1 patient with IRAK4 deficiency and 3 patients with NEMO (300248) deficiency causing X-linked hyper-IgM immunodeficiency with ectodermal dysplasia (300291), 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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