Diagnostic Considerations
Atopic dermatitis is the primary alternative diagnosis. Atopic dermatitis is clinically characterized by a somewhat different appearance than the dermatitis in patients with HIES. Frequent weeping, superinfected lesions are seen in patients with atopic dermatitis, whereas indurated boils and abscesses are seen in HIES subjects.
Other primary immunodeficiencies with eczematous dermatitis include Wiskott-Aldrich syndrome (WAS) and chronic granulomatous disease (CGD). Patients with these disorders tend to not have dermatitis as severe as that seen in HIES patients and lack the facial and skeletal abnormalities associated with AD HIES. Patients with WAS have bleeding complications (eg, bloody diarrhea, CNS bleeding) secondary to thrombocytopenia and platelet dysfunction; platelet size is small in WAS. Patients with CGD do not develop pneumatoceles, although staphylococcal pneumonias are common, and their clinical features are characterized by granulomatous lesions involving multiple organs.
Omenn syndrome (OS), a severe combined immunodeficiency disease (SCID) variant, is a syndrome caused by hypomorphic mutations of multiple genes associated with SCID. Erythroderma presents in OS is essentially the same as seen in graft versus host disease and their clinical features are also characterized by diarrhea, hepatosplenomegaly, hypereosinophilia, and markedly elevated serum IgE levels but low or absent other Ig isotypes.
Hypomorphic mutations of genes associated with OS include those causing SCID with RAG1 and RAG2 hypomorphic mutations being the most common. Absolute lymphocyte count is elevated because of activated oligoclonal and autoreactive T cells, but they are poorly responsive to mitogens or specific antigens; also, B cells are absent. This condition is fatal if not treated with hematopoietic stem cell transplantation.
Common variable immunodeficiency disease (CVID) is often accompanied by eczema and other atopic features, but the eczema is usually milder than that seen in HIES, and the facial and skeletal anomalies are absent. In general, patients with CVID do not demonstrate elevated IgE levels. Staphylococcal keratoconjunctivitis is observed in both diseases.
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome is characterized by early-onset insulin-dependent diabetes mellitus (IDDM), severe enteropathy (watery or bloody diarrhea, failure to thrive [FTT], extensive food allergy), and eczema/erythroderma/alopecia with elevated IgE levels. Autoimmune phenomena also include thyroid grand, CNS, and hematological system. This is an X-linked recessive disorder associated with mutation of FOXP3, resulting in impaired development of CD4+ CD25+ regulatory T cells in the thymus, which result in impaired peripheral tolerance. IPEX patients are ill from early infancy. Primary immune deficiencies with aberrant IgE production were reviewed by Ozcan et al. [34] CBM-opathies that are caused by mutations of genes encoding proteins composing CBM complexes can also manifest some overlapping clinical features of HIES, including severe eczema, elevated serum IgE, and vulnerability to fungal and Staphylococcal infections. [35]
The secondary immunodeficiency that may have features of HIES is human immunodeficiency virus (HIV) infection. Some patients with HIV develop extremely high IgE levels, show clinical signs and symptoms of allergy, and have high IL-4 production, but such clinical manifestation become less common after introduction of highly active anti-retroviral therapy (HAART).
Differential Diagnoses
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Wiskott-Aldrich Syndrome
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Chest radiograph of a patient with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES) and a lung abscess following multiple staphylococcal pneumonias. Aspergillus fumigatus was isolated from the abscess.
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Father and daughter with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the father's distinctive facies with prominent forehead, deep-set eyes, broad nasal bridge, and wide interalar distance.
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Mother and son with autosomal dominant (AD) hyperimmunoglobulin E syndrome (HIES). Note the mother's distinctive facies. She had a history of multiple deep-seated abscesses that took months to heal after incision and drainage.
