Hyper-immunoglobulin E syndrome (HIES) is a multisystem immunodeficiency disorder characterized by recurrent eczematoid rash, pulmonary and skin infections, and markedly elevated serum-IgE levels. The inherited form is uncommon and is classified into two types. Type-1 HIES (Job syndrome) is autosomal dominant (AD-HIES) and includes immune system abnormalities along with vascular, skeletal, and connective tissue abnormalities. Type-2 HIES is autosomal recessive (AR-HIES). In addition to immune system abnormalities, it involves recurrent skin (viral, bacterial) and lung infections more commonly but lacks musculoskeletal abnormalities.[1,2] Elevated serum-IgE levels may be seen in various conditions; hence, its diagnosis requires a high degree of suspicion and typical clinical features. This case series of six children highlights various presentations and management of HIES in children.
A 2-year-old male child, born out of consanguineous marriage, had a history of recurrent generalized erythematous rash with occasional pustules over the body since 10 months of age. He had a history of hospitalization twice for pneumonia and erythroderma, which were managed with injectable antibiotics. There was involvement of ~60% body surface area (BSA) involving face, trunk, and extremities with multiple erythematous, hyperpigmented papules and plaques with mild scaling. Lips showed hyperpigmentation, scaling, and crusted erosions. He had mild dysmorphic features with prominent forehead, broadened nasal bridge, and slightly thick skin [Figure 1a and b]. Palms and soles showed diffuse scaling, crusting, and erosions [Figure 1c and d]. On evaluation, he had leukocytosis (34,070 cells/mm3) with absolute eosinophil count (AEC) of 20,101 cells/mm3 and raised serum-IgE levels (16,000 IU/mL). Histopathology was suggestive of eczematous dermatosis.
The child was managed as severe atopic dermatitis (AD) with wet-wrap therapy, emollients, topical corticosteroids (TCS), and cyclosporine to which he responded poorly. A possibility of immunodeficiency syndrome was considered. Genetic studies revealed pathogenic homozygous deletions of exons 15 to 18 (Transcript: NM_203447) in DOCK8 gene which confirmed type-2 AR-HIES, and bone marrow transplant (BMT) was done successfully. However, he developed lower respiratory tract infection and died two months after BMT. Both the parents were found to be carriers of DOCK8-gene deletion mutation.
A 2-year-old male child was brought with recurrent red painful rash over body since seven months of age and history of hospital admissions thrice for respiratory illnesses which were treated with antibiotics. He had multiple ill-defined scaly erythematous plaques with oozing, crusting, and pustules over body [Figure 2a and b], AEC of 1,872 cells/mm3, and raised serum-IgE levels (8,700 IU/mL). Skin biopsy was suggestive of chronic eczematous dermatosis [Figure 2c]. He was treated with syrup prednisolone, oral antibiotics, antihistamines, emollients, and bleach-bath to which he responded poorly. He was clinically diagnosed as likely a case of AR-HIES and was started on trimethoprim–sulfamethoxazole prophylaxis for recurrent infections at 10 mg/kg/day, topical emollients, and TCS. This significantly reduced the severity of cutaneous lesions and frequency of respiratory infection.
A 2-month-old infant admitted for acute pneumonia had history of recurrent episodes of itchy erythematous scaly plaques, occasional pustules, vesicles, and bullae over extremities since day five of life [Figure 3a and b]. She had leukocytosis (23,000 cells/mm3), elevated AEC (9,400 cells/mm3), and serum-IgE levels (2,600 IU/mL). Pus culture isolated methicillin-resistant coagulase-negative Staphylococcus. Blood culture isolated Klebsiella pneumonia. He was treated with parenteral antibiotics, emollients, and short-course oral steroids. The skin lesions responded well with post-inflammatory hyperpigmentation and minimal scarring at few sites.
A total of six cases, including the above-mentioned, are summarized in Table 1. All had recurrent eczematoid rash responding poorly to conventional treatment, secondary infection, multiple hospitalizations, and raised serum-IgE levels.
Hyper-immunoglobulin E syndrome is a rare primary immunodeficiency syndrome. Majority of cases occur sporadically; however, it may be inherited too. AD-HIES usually involves mutation in STAT3, whereas AR-HIES commonly involves DOCK8 gene.[3,4] Due to unavailability and financial constraints, we could carry out genetic studies in only one case who had DOCK8 gene mutation. However, clinically most of our cases had features favoring type-2 AR-HIES in view of recurrent skin (viral, bacterial) and lung infections.
It commonly involves scalp and face and usually present early in life or even at birth.[5,6] Our case series had six childhood cases of HIES with age ranging from two months to ten years. All had onset in first ten months of life except case 6 with late onset at two years. All children had almost similar presentation with variable severity of recurrent eczematoid rash with secondary infection that progressed to erythroderma in two cases requiring hospitalization. One case had occasional vesicles, bullae, and crusted plaques over extremities. Two had prominent involvement of scalp and face, in addition to trunk and extremities which was the predominant pattern seen in rest of the cases.
Sinopulmonary infections like recurrent pneumonia are common and >50% may have ≥3 episodes, and Staphylococcus aureus, Haemophilus influenzae, Streptococcus pneumonia, and occasionally fungus are implicated.[7–9] All our cases had history of 1–3 episodes of hospitalization for pulmonary infection treated with antibiotics. One had food allergy, whereas two had history of bronchial asthma.
Characteristic musculoskeletal abnormalities and facial features may be seen usually during late childhood involving prominent forehead, wide-set eyes, broadened nasal bridge, high-arched palate, coarse skin, and delayed shedding of primary dentition. Only one child had mild dysmorphic features here. Case 6 had fracture humerus twice at the age of three and five years, respectively, following insignificant trauma in the form of fall while walking.
Serum-IgE levels are usually >2000 IU/mL and elevated AEC may be seen in ~90%; however, the specificity of IgE is uncertain and eosinophilia too does not correlate with rise in serum-IgE. All six cases in our series had significantly raised serum-IgE levels and AEC.
Atopic dermatitis is the commonest differential diagnosis and may be distinguished based on the presence of various immunological and non-immunological features. The main goal of management in HIES is aggressive treatment of infections and optimum skin care. Staphylococcal infection is thought to be the main driver of dermatitis. Almost all our patients received multiple courses of antibiotics, oral, and TCS intermittently. Hematopoietic stem cell transplantation (HSCT) has been tried in both dominant and recessive forms; however, its role is more favored in recessive form with significant reduction in cutaneous lesions, recurrent infections, and elevated IgE. Case 1 underwent BMT but succumbed to lower respiratory tract infection after two months.
Our case series highlights various characteristics, presentation, and management of this rare syndrome in childhood cases. AR-HIES subtype may be more common in skin-of-color; however, large-scale studies are required to establish the same. Awareness of these manifestations may facilitate early identification and contribute to optimal care of patients as representative data on the same is limited in literature.
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The parents/caretakers of patients in this manuscript have given written informed consent to the publication of their case details and photographs.
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Conflicts of interest
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