Hyperimmunoglobulin E syndrome - Report of a rare case with review of literature

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A 5-year-old boy presented with a history of recurrent pyogenic infections involving the head and neck region since infancy. He had experienced three bouts of pneumonia, all of which were effectively treated with antibiotics. Clinical examination revealed characteristic facial deformity comprising a prominent forehead, broadened nasal bridge, sparse scalp hair, and slightly thick skin, along with scaling, papulopustular eruptions, and a few crusted erosions [Figures 1 and 2]. His parents provided a surgical history of cervical lymph node excision subsequent to a cold abscess [Figure 3]. There was no family history of similar illness or known consanguinity.

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Figure 1:

Dysmorphic face.

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Figure 2:

Papulopustules and crusted erosions involving head and neck.

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Figure 3:

Surgically excised cervical lymph node following cold abscess (arrow mark)

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Laboratory investigations demonstrated hemoglobin – 11.2 g/dL, total leukocyte count – 11,000/cumm (neutrophils 70% and eosinophils 11%), and a raised erythrocyte sedimentation rate. Notably, serum immunoglobulin E (IgE) levels were markedly elevated at 3289 IU/mL. Liver and renal function tests were within normal limits. Chest radiograph revealed bilateral patchy opacities, which were claimed to be remnants of previous pneumonic episodes by the pulmonologists. We made an orthopedic referral to screen for osteopenia, and no evidence of osteopenia was noted at this time.

The clinical presentation and history of recurring infections, combined with markedly elevated IgE levels, were strongly suggestive of Autosomal Dominant Hyper-IgE syndrome (AD-HIES). A Signal Transducer and Activator of Transcription 3 (STAT3) mutation was considered likely, although genetic confirmation could not be done due to financial constraints.

AD-HIES is typically caused by heterozygous mutations in the STAT3 gene on chromosome 17q21, leading to impaired Th17 differentiation, reduced neutrophil chemotaxis, and altered cytokine signaling, particularly interleukin (IL)-6 and IL-17 pathways.^[1] Reduced interferon-gamma production in HIES contributes to elevated IgE levels by failing to suppress Th2-mediated class switching and IgE overproduction. The serum IgE level is usually >2000 IU/mL in such patients. Early-onset eczematous dermatitis, recurrent cold staphylococcal abscesses, mucocutaneous candidiasis, and chronic xerosis with folliculitis comprise the characteristic cutaneous presentation of hyper-IgE syndrome.^[2]

Extracutaneous presentations are commonly pulmonary (recurrent pneumonia, pneumatocele, and bronchiectasis), skeletal (scoliosis and pathological fractures), along with dental anomalies such as retained primary teeth and high arched palate.^[3] Recently, Patel et al. reported unusual comorbidities in their cohort of patients with hyper-IgE syndrome, such as multiple endocrinopathies, pyoderma gangrenosum, and dermatomyositis, which were diagnosed very late in life.^[4] A recent compilation of Indian national data revealed recurrent skin abscesses (77.7%) to be the most common complication in hyper-IgE syndrome, followed by pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), Mycobacterial infections (18.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%).^[5]

Autosomal recessive hyper-IgE syndrome, which is less common than AD-HIES, is characterized by severe viral infections, neurologic complications, high malignancy risk, and lacks the skeletal and dental abnormalities seen in AD-HIES.

The differential diagnoses of HIES is broad and includes several genetic syndromes and inborn errors of metabolism that present with refractory eczema and elevated IgE levels^[6-9] [Table 1]. These disorders demonstrate the heterogeneity of hyper-IgE phenotypes, with significant overlap between metabolic/genodermatoses and immunological deficits. Accurate diagnosis of AD-HIES relies on a high National Institute of Health (NIH) clinical score (>40), supported by Th17 cell counts and STAT3 sequencing, with genetic testing essential to differentiate overlapping conditions.^[7]

The treatment is largely symptomatic, including antibiotic prophylaxis, dermatological care, and multispecialty surveillance. Hematopoietic stem cell transplantation may be a viable option for severe autosomal recessive disorders like DOCK8 (dedicator of cytokinesis 8) deficiency. Wakim et al.^[10] concluded that intravenous immunoglobulin was not beneficial in such patients and did not significantly decrease IgE levels or IgE synthesis. Ongoing research on gene therapy and biologics (dupilumab) has shown promise for more definitive management in the future.^[11]

This case has been reported to increase awareness about this uncommon condition, to facilitate its early diagnosis and management.