CASE 10

Barry is 16 months of age and since his adoption at birth has been hospitalized on several occasions with multiple and severe gram-positive bacterial infections of the respiratory tract, skin, soft tissues, gastrointestinal tract, and even bones. On two occasions he has suffered from meningitis, and on at least one occasion he developed nearly overwhelming septicemia, with systemic spread of gram-negative bacteria. Laboratory analysis at the time of these various infections indicated that he had had infections with Mycobacterium avium, as well as with both gram-positive (Streptococcus pneumoniae, Staphylococcus aureus) and gram-negative (Haemophilus influenzae and Pseudomonas aeruginosa) organisms.

Interestingly, despite childhood immunization with H. influenzae, as well as infection with S. pneumoniae and H. influenzae, there was a dearth of specific antipolysaccharide antibodies, probably contributing to the susceptibility to encapsulated bacteria. IgM levels were elevated, with a slight diminution in IgG and IgA levels. Levels of T cells and B cells and macrophages/neutrophils were normal, as was the subset distribution of T cells and the surface expression of CD40L/CD154 (see Case 4). Analysis of phagocyte function (see Case 6) and proliferation of mitogen-stimulated T cells were at the low end of normal (see Case 2). NK cell levels were normal, with evidence for some decrease in killing function (˜threefold on a cell-for-cell basis compared with normal).

Physically, Barry had multiple morphogenetic abnormalities, including dry skin, sparse hair, and abnormally shaped teeth. Notably, despite the hot summer spell, there was no evidence of sweat and when Barry cried tearing did not occur. Detailed examination of the possible defects in this child at a specialist immunogenetics clinic suggested this was an example of an X-linked hypohidrotic/anhidrotic ectodermal dysplasia syndrome with immunodeficiency (XL-EDA-ID/EDA-ID), now known to represent one of a family of similar disorders with genetic aberrancy in intracellular NFκB signaling.

QUESTIONS FOR GROUP DISCUSSION

1. Once again, we are faced with a patient who has recurrent bacterial infections. Based on previous cases, what types of defects would you initially want to consider?

2. The initial blood work indicated normal numbers of cells indicating that this problem is not one of cell development. However, analysis of serum immunoglobulin indicated a decrease in all antibody isotypes and an increase in IgM. These results are similar to those described for the patient in Case 4. What test would you perform to rule out, or confirm, that Barry has (or does not have) the same disorder?

3. On the basis of the tests in question 2, we have ruled out hyper IgM syndrome as a possible diagnosis. Because Barry has a history of infections with both gram-negative and gram-positive bacteria, what TLRs would you investigate?

4. Results of investigations of TLRs revealed that both TLR2 and TLR4 expression was normal. On consultation with an internist you learn that Barry’s morphogenetic abnormalities are consistent with hypohidrotic/anhidrotic ectodermal dysplasia (HED/EDA). Over 150 distinct phenotypes have been classed as ectodermal dysplasia. What is the most common defect in this disorder?

5. Three forms of ectodermal dysplasia are known to result from defects in NFκB signaling pathway. Review the activation of NFκB. Include the following in your discussion: (a) serine kinase complex: IKKα, IKKβ, IKKγ (NEMO); (b) phosphorylation, ubiquitination, degradation; (c) IκB, NFκB dimer; and (d) translocation and transcription. What is the role of NFκB in immunity and inflammation?

6. Explain how a mutation in NEMO (see question 5) would affect the activation of NFκB.

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