Evolving neonatal rash and other clues: A dermatology perspective on early diagnosis of hyper-immunoglobulin E syndrome

INTRODUCTION

Autosomal dominant hyper-IgE syndrome (AD-HIES) is a primary immunodeficiency resulting from loss-of-function STAT3 mutations.^[1] Inflammatory skin lesions, cutaneous infections (candidiasis, staphylococcal), pneumonias, skeletal abnormalities, eosinophilia, and high IgE levels are characteristic features of this disease.^[2] Skin lesions are the earliest manifestation, with onset in the neonate or early infancy, which can lead to an early diagnosis.^[3,4]

CASE REPORT

A one-month-old term male with various congenital anomalies [Table 1] presented with erythematous papulovesicles with yellowish crust over the scalp, face, and neck of 1 week’s duration. Oral antibiotics, followed by mild topical steroids (desonide 0.05% cream), led to a transient improvement. Skin biopsy was performed at 6 weeks due to the occurrence of multiple new lesions, revealing spongiotic dermatitis.

Exacerbation was noted at three months with the occurrence of numerous papulo-pustules over the head and neck, in addition to multiple clear vesicles over the hands and feet [Figure 1a-c]. Other findings included oral and inguinal candidiasis, leukocytosis, and mild eosinophilia. In the absence of systemic complaints, the infant was kept under close clinical follow-up with continued mild topical steroids for the head and neck, and topical azoles were added for candidiasis.

Close

Figure 1:

(a) Erthematous papules over the cheek, pinna and scalp; (b-c): Clear vesicles over the feet at three months of age.

Export to PPT

At four months, a 6 × 6 × 4 cm fluctuant swelling developed over the nape of the neck without tenderness, warmth, erythema, or pyrexia. Skin lesions included yellowish scalp scaling, psoriasiform lesions over the back, and papulo-pustules over the head and flexures [Figure 2a-d]. Aspiration of the swelling revealed pus, indicating a cold abscess, which grew methicillin-resistant Staphylococcus aureus. Blood counts showed rising leukocytosis and eosinophilia. Based on the skin lesions, staphylococcal cold abscess, and eosinophilia, a diagnosis of AD-HIES was considered. Further assessment revealed facial dysmorphism and markedly raised serum IgE. Exome analysis revealed a known pathogenic heterozygous missense STAT3 variant, confirming the diagnosis. The details of the disease course, differentials considered, and investigations are elaborated in Table 1.

Close

Figure 2:

(a) Cold abscess over the nape of the neck with papulovesicles and pustules over the scalp; (b) Psoriasiform papules and plaques over the back; (c) Thick yellowish scaling over the scalp; (d) Erythematous papules over the cubital fossa.

Export to PPT

The abscess resolved with a course of intravenous linezolid and serial aspirations. The psoriasiform lesions resolved rapidly following a course of oral fluconazole, confirming the diagnosis of a candidal id reaction. Following pediatric and immunology consults, trimethoprim-sulfamethoxazole prophylaxis (2 mg/kg trimethoprim daily) was initiated along with bleach baths and topical agents (mometasone furoate 0.1% cream, tacrolimus 0.03% ointment) for the skin lesions. Since the serum immunoglobulin levels were normal and there were no major systemic infections, immunoglobulin replacement therapy was not initiated at this point.

At six months, facial dysmorphism had become more evident [Figure 3], skin lesions were persistent but mild, and there were recurrent episodes of oral candidiasis treated with courses of oral fluconazole. The child remained on regular immunology and dermatology follow-up but expired following an episode of bacterial pneumonia at the age of 3 years.

Close

Figure 3:

Marked facial dysmorphism at 6 months: Frontal bossing, broad nasal root, and hypertelorism.

Export to PPT

DISCUSSION

Diagnosis of AD-HIES is often delayed because most characteristic clinical features manifest late.^[5-7] In 103 patients from India, the mean age at diagnosis was 7.4 years (6 months–27 years).^[6] Early clinical suspicion and diagnosis of HIES are crucial for the initiation of supportive measures, which can prevent major infections and reduce mortality.^[5]

Skin lesions are the earliest manifestations of HIES, appearing in the neonatal period or early infancy.^[3,4] These are described as papulopustular or papulovesicular lesions predominantly over the face and scalp, which can also involve flexures (neck, axilla, and groin); with eosinophilic folliculitis or eosinophilic spongiosis in histology.^[3,4,8] The typical morphology of extensive atopiform eczema develops later.^[3,8] Recurrent candidial and staphylococcal infections invariably complicate skin lesions.^[3] The folliculocentric papular rash is hypothesized to result from a dysregulated immune response to staphylococcal and candidial antigens.^[3,4]

Our patient had such a papular rash from 3 weeks of age, along with the unusual finding of clear vesicles over the acral regions, which has not been reported previously in association with this syndrome. Initially, the rash morphology and spongiosis in histology suggested a diagnosis of seborrheic dermatitis. Later, as the lesions persisted and worsened, Langerhans cell histiocytosis (LCH) was considered a possibility. However, a repeat skin biopsy and evaluation for the extra-cutaneous manifestations of LCH ruled out this possibility [Table 1]. The development of a characteristic staphylococcal cold abscess with eosinophilia at 4 months of age raised the suspicion of AD-HIES, which was reinforced by the presence of mucocutaneous candidiasis, facial dysmorphism, and idiopathic leukocytosis.^[3,9] Our patient also exhibited multiple congenital anomalies [Table 1], which have not been previously reported and are likely incidental.

Staphylococcal cold abscesses have been reported as early as 15 days of life.^[3,9] Skeletal features such as facial dysmorphism and osteopenia have been occasionally described in infancy,^[3,9] but usually manifest later.^[5] Leukocytosis without fever or systemic illness is common in association with the papulopustular rash in neonates and infants and is an early marker.^[3] Peripheral eosinophilia is an inconsistent finding in early life, although it has been reported as early as 2 months.^[3,9] Serum IgE levels are an unreliable marker of HIES in infancy, with levels often remaining normal up to 2 years of age. Even when levels are elevated, titers are typically not above 2000 IU/nL in the first few years.^[3,8] In our patient, non-specific leukocytosis and subtle facial dysmorphism accompanied the early rash but went unnoticed in the absence of clinical suspicion.

Life-threatening infections such as necrotizing pneumonia and pneumatoceles are not uncommon in HIES in the first few years of life. Although definitive treatments, such as bone marrow transplant and gene therapy, are not widely used or available, early diagnosis and initiation of supportive measures can significantly improve the course.^[3,7]

CONCLUSION

AD-HIES should be suspected when neonates/infants present with persistent papulovesicular lesions over the head and flexures. These can mimic various inflammatory or infiltrative dermatoses of this age group, including seborrheic dermatitis and LCH.^[4] Dermatologists can make a significant contribution by recognizing these lesions in neonates and infants, leading to the early diagnosis of AD-HIES.^[3,4]

Other early markers include idiopathic leukocytosis, which often accompanies the early skin lesions. Eosinophilia and IgE levels are unreliable markers in early life.^[3,9]