Immunodeficiency 68D81.4

Immunodeficiency-68 is an autosomal recessive primary immunodeficiency caused by a mutaion in the MYD88 gene. Clinically, the clinical picture is characterized by severe systemic and invasive bacterial infections beginning in infancy or early childhood. The most common pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas, but other pathogens may be present. IMD68 is life-threatening in infancy and early childhood. The first invasive infection usually occurs before 2 years of age, with meningitis and upper respiratory tract infections being common manifestations. Mortality in early childhood is high, with most deaths occurring before age 8 years. Affected individuals have an impaired inflammatory response to infection, including absent fever and neutropenia. C-reactive protein may be elevated. General immunologic examination is usually normal, with normal levels of B cells, T cells, and NK cells. However, extended studies indicate an impaired cytokine response to lipopolysaccharide (LPS) and IL1B (147720). Patients have good antibody responses to most vaccines. Viral, fungal, and parasitic infections are generally not observed.

At the molecular level, IMD68 results from impaired function of selective Toll receptor signaling pathways that ultimately activate NFKB (164011) to produce cytokines (Picard et al. 2010).

Prog: Many of them died of the disease, all before the age of 8 and most before the age of 2. Prophylactic treatment with antibiotics and IVIG had a positive effect on survival. Clinical status and outcome improved with age, especially in adolescence. Picard et al (2010) pointed out the low susceptibility to certain bacterial infections and emphasized that early diagnosis is crucial for initiating treatment.

Early detection in early childhood is critical, as prophylactic treatment with IVIG or antibiotics is effective.

Picard et al (2010) reported 12 patients from 6 unrelated families with IMD68. The families were from different countries of origin; 2 were consanguineous.

Most patients developed early-onset invasive bacterial infections, including meningitis, sepsis, arthritis, osteomyelitis, and deep tissue abscesses. Noninvasive skin or upper respiratory tract infections were also observed. The most common pathogens were Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Less common were H. influenzae, Salmonella, group B streptococci, and Moraxella. Affected individuals had an impaired inflammatory response, such as low or absent fever and low leukocyte and neutrophil levels; C-reactive protein levels were variable.

Lab: Immunologic studies 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 showed good antibody responses to vaccination, including pneumococcal. Functional studies of patient cells show impaired cytokine responses to TLR and IL1R agonists, for example, with low IL6 and TNFA production.

1. Conway DH et al (2010) Myeloid differentiation primary response gene 88 (MyD88) deficiency in a large kindred. (Letter) J Allergy Clin Immun 126: 172-175.
2. Picard C et al (2010) Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency. Medicine 89: 403-425.
3. Platt CD et al (2019) A novel truncating mutation in MYD88 in a patient with BCG adenitis, neutropenia and delayed umbilical cord separation. Clin Immun 207: 40-42.
4. von Bernuth et al. (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321: 691-696.