A number sign (#) is used with this entry because of evidence that immunodeficiency-68 (IMD68) is caused by homozygous or compound heterozygous mutation in the MYD88 gene (602170) on chromosome 3p22.

Immunodeficiency-68 (IMD68) is an autosomal recessive primary immunodeficiency characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common organisms implicated are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, although other organisms may be observed. IMD68 is life-threatening in infancy and early childhood. The first invasive infection typically occurs before 2 years of age, with meningitis and upper respiratory infections being common manifestations. 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. Viral, fungal, and parasitic infections are generally not 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, IMD68 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 Picard et al., 2010).

See also IMD67 (607676), caused by mutation in the IRAK4 gene (602170), which shows a similar phenotype to IMD68. 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).

Von Bernuth et al. (2008) reported 9 children from 2 consanguineous and 3 nonconsanguineous kindreds with IMD68. The families originated from France, Turkey, Portugal, and Spain. In infancy, the children developed life-threatening, often recurrent, pyogenic bacterial infections, including invasive pneumococcal meningitis. Other organisms included Pseudomonas and Staphylococcus aureus. Many patients had upper respiratory infections, such as pharyngitis, adenitis, and deep tissue abscesses. The patients had a poor inflammatory response to the infections, with no fever and low white blood cell counts. C-reactive protein levels were variable. Three children died between 1 and 11 months of age, and the 6 surviving children were between 3 and 16 years of age. Basic immunologic workup was essentially normal, but detailed functional studies of patient cells showed impaired cytokine response to most Toll-like receptors and IL1B. After stimulation, patient cells failed to produce IL6, IL8, TNFA, and interferons. Response to LPS was variable, and response to poly(I:C) and TNFA was normal. These children were otherwise healthy, with normal resistance to other microbes, and their clinical status improved with antibiotic prophylaxis and age.

Conway et al. (2010) reported a large consanguineous family in which 7 members were confirmed to have IMD68 by genetic analysis. The proband presented in the first weeks of life with Pseudomonas-associated meningitis. He did not have associated fever or increased white cell count. Detailed immunologic studies showed impaired cytokine response to Toll-like receptors, with decreased production of TNFA, IL6, and IL1B. Other affected individuals presented in infancy with numerous severe invasive infections, often with Pseudomonas, but also pneumococcus and Staphylococcus aureus. They too had poor inflammatory responses with lack of fever and low white cell counts. The patients were maintained on IVIg with apparent improvement of the infections. Two adults in the family lacked TLR responses in vitro, but had no history of life-threatening bacterial infections. However, 2 additional, presumably affected family members died in early infancy of pneumococcal meningitis.

Picard et al. (2010) studied 12 patients from 6 unrelated kindreds with IMD68. Nine patients from 5 families (families a-e) had previously been reported by von Bernuth et al. (2008). An additional patient from family a and 2 sibs (family f) were reported for the first time. The families were from various countries of origin; 2 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 vaccination, including to pneumococcus. 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 Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Less common organisms included H. influenzae, Salmonella, group B strep, and Moraxella. Affected individuals had an impaired inflammatory response, such 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 TNFA production. Many died of the disease, all before 8 years of age, and most before 2 years. Prophylactic treatment with antibiotics and IVIg were 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.

Platt et al. (2019) reported a boy, born of consanguineous Omani parents, with IMD68. He had delayed separation of the umbilical cord at 4 weeks of age and developed BCG adenitis after vaccination. At age 5 months, he developed Pseudomonas pneumonia and a MRSA-positive abscess. Immune evaluation was notable for severe neutropenia, decreased B cells, and reduced IgM. Patient cells showed impaired production of IL6 and TNFA after stimulation with IL1B, LPS, and certain Toll-like receptors. The authors postulated that decreased TNFA may have increased susceptibility to mycobacterial infection in this patient. He was maintained on prophylactic antibiotics. A similarly affected brother had died at age 7 months of Pseudomonas sepsis; he had no fever.

The transmission pattern of IMD68 in the families reported by von Bernuth et al. (2008) was consistent with autosomal recessive inheritance.

In 9 children from 5 families with IMD68, Von Bernuth et al. (2008) identified 3 different biallelic mutations in the MYD88 gene. Four children from 3 kindreds were homozygous for in-frame deletion of glu52 (E52del; 602170.0001). Two sibs were homozygous for a missense mutation (R196C; 602170.0002), and 1 child was compound heterozygous for 2 missense variants (R196C and L93P, 602170.0003). Two sibs who died in infancy were presumably homozygous for the same E52del mutation found in their surviving brother. The mutations were not found in healthy controls, and all affected conserved residues. Functional analysis using patient fibroblasts and expression of wildtype or mutant alleles in cell lines confirmed that all 3 MYD88 mutations resulted in loss of function and led to complete MYD88 deficiency. Von Bernuth et al. (2008) concluded that, like IRAK4 deficiency (IMD67; 607676), MYD88 deficiency abolishes most cytokine responses to Toll-like receptor (see 603030) stimulation.

In affected members of a large consanguineous family with IMD68, Conway et al. (2010) identified a homozygous nonsense mutation in the MYD88 gene (E66X; 602170.0005). Western blot analysis of patient cells showed absence of the MYD88 protein. Detailed immunologic studies showed impaired response to most Toll-like receptor stimuli, with significantly decreased production of TNFA, IL6, and IL1B compared to controls. The phenotype was notable for cutaneous and systemic Pseudomonas infection as well as for pneumococcal meningitis.

In a boy, born of consanguineous Omani parents, with IMD68, Platt et al. (2019) identified a homozygous nonsense mutation in the MYD88 gene (R272X; 602170.0006). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was found only in heterozygous state at a low frequency in the gnomAD database (1.19 x 10(-5)). Patient cells had no detectable wildtype or truncated MYD88 protein. Functional studies of patient fibroblasts showed impaired cytokine response to LPS, certain Toll-like receptors, and IL1B, whereas response to poly(I:C) and TNFA was normal.

Von Bernuth et al. (2008) noted that the immunologic phenotype of the 9 children they reported with IMD68 due to MYD88 deficiency was similar to that of Myd88-deficient mice (see ANIMAL MODEL in 602170), but the infectious phenotype was different. The MYD88-deficient patients were susceptible to Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae, but were normally resistant to most other infectious agents. In contrast, Myd88-deficient mice had been shown to be susceptible to almost all pathogens tested.