Beyond Eczema: An Atypical Case of Hyperimmunoglobulin E Syndrome

Dear Editor, Hyperimmunoglobulin E syndrome (HIES) refers to a group of primary immunodeficiency disorders, characterized by a triad of eczema, increased susceptibility to cutaneous and pulmonary infections, and elevated immunoglobulin (Ig) E levels. The annual incidence of HIES is estimated at around 1 in 1,000,000 and it affects males and females equally.[1] The prototype of these rare disorders is the Job syndrome or autosomal dominant HIES (AD-HIES) caused by heterozygous loss-of-function mutation in signal transducer and activator of transcription-3 (STAT3) gene.[2] Autosomal recessive and X-linked variants of the syndrome have also been described. Hereby, we present the case of a 4-year-old female child with HIES confirmed by a heterozygous loss-of-function mutation in the STAT3 gene. A 4-year-old female child, born of nonconsanguineous parentage presented to our department with a history of recurrent skin infections and a pruritic eruption involving the face, trunk, and limbs. The child was previously diagnosed with extensive tinea corporis and had suffered from multiple episodes of otitis media in the past. The child had also been hospitalized in the past for empyema thoracis and severe colitis. Physical examination revealed a coarse facial appearance [Figure 1]. Multiple eczematous lesions were seen on the scalp, face, neck, upper back, upper limbs, and buttocks [Figures 2 and 3]. The child also had erythema and edema of the eyelid margins suggestive of bilateral blepharitis. Examination of the nails revealed the signs of acute paronychia in the left first toenail. Laboratory investigations revealed a markedly elevated serum IgE level (2314 IU/mL) with normal levels of IgG, IgA, and IgM. The eosinophil count was found to be within the normal limits. The chest radiograph of the child revealed a thin-walled cystic space within the right lung parenchyma, consistent with a pneumatocele. Histopathological assessment using hematoxylin and eosin staining of a punch biopsy taken from the eczematous skin lesions revealed features consistent with chronic dermatitis with concomitant folliculitis. In view of the clinical picture and laboratory findings, the child was diagnosed as having HIES. Genetic testing confirmed a heterozygous missense variant in exon 13 of the STAT3 gene resulting in the amino acid substitution of glutamine for arginine at codon 382, hence confirming the diagnosis [Supplementary Figure 1]. The child was put on anti-staphylococcal antibiotic prophylaxis (trimethoprim–sulfamethoxazole) and itraconazole. Hematopoietic stem cell transplantation is being planned for the child.Supplementary Figure 1: Genetic test report confirming the diagnosis. STAT3: Signal transducer and activator of transcription-3Figure 1: Coarse facies; eczematous lesions over the face and neckFigure 2: Multiple eczematous lesions over the scalp and upper backFigure 3: Excoriated papules and eczematous plaques over back and buttocksHIES stands as a fascinating enigma within the realm of immunodeficiency disorders. It presents with several immunological aberrations blending with a diverse array of clinical manifestations. The classic autosomal dominant variant of HIES is attributed to the heterozygous mutations with a dominant negative effect in the STAT3 gene. STAT3 defects lead to impaired Th17 cell differentiation and interleukin-17 production and are associated with increased susceptibility to bacterial and fungal infections. HIES presents with a heterogeneous clinical spectrum, neonatal-onset eczema, recurrent cutaneous staphylococcal infections with abscess formation, and recurrent bacterial and fungal pneumonia being the most common presentations. Pneumatoceles and bronchiectasis commonly form during the healing process of pneumonia and usually persist once the infection has cleared.[3] Mucocutaneous candidiasis and deep organ abscesses are also frequent findings. Skeletal abnormalities such as scoliosis, pathological fractures, hyperextensibility of joints, and retained primary teeth are commonly observed in patients with HIES.[4] Several patients exhibit characteristic facial features such as prominent forehead, broad nasal bridge, and deep-set eyes. In addition, vascular abnormalities in the form of arterial aneurysms are being recognized as an important aspect of HIES.[5] Elevated serum IgE and eosinophilia are the two most consistent laboratory findings in HIES. Eosinophilia is almost always observed in these patients at least at some point which was, however, absent in our patient. Serum IgE is usually markedly elevated (>2000 IU/mL) but has been observed to decrease or even normalize during adulthood.[1] Most cases of AD-HIES are caused by STAT3 mutations. The heterozygous missense variant observed in our patient has previously been reported in patients affected with HIES and lies in the HCO3-transporter family domain of the STAT3 protein.[2] The therapeutic approach primarily focuses on preventing and managing infections. Each infection episode necessitates a complete course of antibiotics such as penicillins and cephalosporins, tailored to the culture and sensitivity report. Extended prophylactic antibiotic therapy targeting Staphylococcus aureus plays a crucial role in averting severe, debilitating infections, and mitigating lung tissue damage. Patients may benefit from immunological correction by high-dose intravenous Igs and hematopoietic stem cell transplantation. Being a complex and multifaceted group of disorders, HIES often poses a diagnostic challenge. Keeping in view the inherent susceptibility of these patients to severe, life-threatening infections, early diagnosis is paramount from a therapeutic perspective. Multidisciplinary management is essential to improve the outcomes and prevent complications in affected individuals. Declaration of consent The authors certify that they have obtained all appropriate consent forms, duly signed by the parent(s)/guardian(s) of the patient. In the form, the parent(s)/guardian(s) has/have given his/her/their consent for the images and other clinical information of their child to be reported in the journal. The parents understand that the names and initials of their child/children will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.