A 9-year-old girl is brought to the office due to persistent nasal drainage. Over the past 2 weeks, the patient has had increasing nasal congestion and drainage. The discharge was initially clear but has become dark and foul smelling over the past few days. The patient has a history of multiple skin abscesses that developed when she was an infant, but they typically do not cause discomfort. She has also had atopic dermatitis since infancy. Temperature is 37.1 C (98.8 F). On examination, the patient is interactive and talkative. Thick nasal discharge appears from both nares. Cardiopulmonary examination is normal. There are several diffuse areas of dry, excoriated skin along the trunk and upper extremities. Results of a complete blood count are as follows:
| Hemoglobin | 11 g/dL |
| Platelets | 200,000/mm3 |
| Leukocytes | 7,500/mm3 |
Which of the following patterns of immunoglobulin production is most likely to be seen in this patient?
Hyper-IgE syndrome | |
Pathogenesis |
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Clinical |
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Laboratory |
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Th17 = T-helper cell type 17. | |
This patient with signs of a sinus infection (eg, thick, purulent nasal drainage) has a history of recurrent skin abscesses and chronic atopic dermatitis. Given her normal platelet count, which excludes Wiskott-Aldrich syndrome, her findings are most consistent with hyper-IgE syndrome (Job syndrome), an autosomal dominant, primary immunodeficiency disorder.
Hyper-IgE syndrome is characterized by impaired JAK-STAT signaling, leading to defective differentiation and function of T-helper cell type 17 (Th17). Th17 cells normally produce IL-17, which activates neutrophils to migrate to the site of infection. Without this cytokine, neutrophil function is impaired, causing recurrent skin and sinopulmonary infections most commonly due to Staphylococcus aureus and Candida albicans. Neutrophil-induced inflammation is absent, so abscesses are often nontender (ie, cold), and patients are typically afebrile with a normal leukocyte count, as opposed to the leukocytosis expected with infection.
In addition to immunodeficiency, chronic atopic dermatitis is a prominent feature of hyper-IgE syndrome and typically begins in early infancy. Colonization of S aureus and C albicans on the skin triggers mast cell histamine release, causing severe pruritus and an eczematous rash. Patients characteristically have eosinophilia and elevated IgE related to the dermatitis, but other immunoglobulin levels are usually normal. A low Th17 count supports the diagnosis, and molecular genetic testing is confirmatory.
(Choice A) All immunoglobulin levels are decreased/absent in X-linked agammaglobulinemia due to impaired B-cell maturation. Severe sinopulmonary and invasive bacterial infections begin in infancy, and failure to thrive is typical. Without immunoglobulin replacement most children will have near fatal infections early in life.
(Choice B) Chronic eczema without an underlying immunodeficiency can cause elevated IgE, and IgG may also be high if the rash is superinfected. However, the affected area would be erythematous and tender, unlike this patient's cold abscess, making isolated atopic disease unlikely.
(Choice C) Hyper-IgM syndrome, in which immunoglobulin class-switching is impaired due to CD40 ligand deficiency, typically presents in infancy with sinopulmonary and opportunistic infections. Recurrent cold skin abscesses do not typically occur.
(Choice E) Selective IgA deficiency can cause recurrent sinopulmonary infections and is associated with an increased risk for atopy. However, skin infections would not be expected.
Educational objective:
Hyper-IgE syndrome is characterized by elevated IgE levels and is caused by impaired neutrophil activation and migration due to a defect in T-helper cell type 17 cells. Typical findings include noninflammatory (ie, cold) abscesses, recurrent sinopulmonary infections, and chronic atopic dermatitis.