Hyperimmunoglobulin E syndrome (HIES) is a complex disorder characterized by markedly elevated serum immunoglobulin E (IgE) levels, serious recurrent staphylococcal infections, mucocutaneous candidiasis, chronic dermatitis, and skeletal and dental abnormalities. Although not a primary phagocyte defect, neutrophils from patients with this syndrome exhibit a variable and at times profound chemotactic defect. HIES was first described in 1966 and was called Job syndrome, in reference to the biblical description of Job as being affected by “sore boils from the soles of his feet unto his crown.” The skin abscesses in patients with HIES lack the erythema that is typical of such lesions and are referred to as cold abscesses. The key features of HIES are described in Table 1. The disorder is rare, affecting fewer than 1 per million population.
Table1. Summary of Signal Transducer and Activator of Transcription 3–Hyperimmunoglobulin E Syndrome
Most cases of HIES result from inherited or sporadic autosomal dominant negative (DN) mutations in signal transducer and activator of transcription 3 (STAT3), a Janus kinase (JAK)-activated transcription factor activated in response to many cytokines and growth factors. These mutations, which are usually a result of missense or in-frame deletions and located primarily in regions of the protein that interact with other proteins or with DNA, inhibit the activity of the wild-type STAT3 allele and result in a complex pattern of altered cytokine signaling and impaired T helper type 17 (Th17) cell differentiation. Mutations in DOCK8, a guanine nucleotide exchange factor, or TYK2, a JAK family member, result in an AR immunodeficiency with some overlap with HIES features but have more profound impairment in lymphocyte functions, leading to a broader risk of infection and other immune dysregulation. DOCK8 deficiency has recently been recategorized from HIES to combined immunodeficiency22 and will not be further discussed in this chapter.
Insights into how STAT3 signaling defects lead to the clinical syndrome characteristic of DN STAT3-HIES are now emerging. Defective responses to IL-6 may account for the minimal inflammatory responses characteristic of HIES, and the enhanced IgE production may reflect dysregulated immune responses secondary to impaired signaling by IL-10, a negative regulator. Th17 cells are important for control of mucocutaneous Candida infection, which is problematic in many patients. In addition, keratinocytes and bronchial epithelial cells are particularly dependent on Th17 cytokines to produce chemokines and antimicrobial peptides, which may explain the predilection for skin and lung infections. The dental and skeletal abnormalities may be related to defective STAT3 signaling in osteo blasts and osteoclasts.
Clinical Manifestations
The clinical manifestations of STAT3-HIES are at times dramatic. Onset is generally in the first 2 months of life and is manifested by chronic dermatitis. By 5 years of age, patients have a history of recurrent skin abscesses, pneumonias, chronic otitis media, and sinusitis. As patients grow older, recurrent staphylococcal pneumonia is a common problem and can be complicated by the formation of pneumatoceles that can become colonized with Pseudomonas aeruginosa or Aspergillus. Septic arthritis, cellulitis, and osteomyelitis are also observed and are usually caused by S. aureus, although other bacterial pathogens have also been found. Patients can have chronic mucocutaneous candidiasis and occasionally exhibit keratoconjunc tivitis, sometimes complicated by corneal scarring. One feature noted in the majority of patients by the time they reach the teenage years is the presence of coarse facial features (broad nasal bridge, prominent nose). Dental and bone abnormalities are also common features of HIES. Delayed or failure to shed primary teeth occur in the majority. Hyperextensible joints and scoliosis are frequent. Osteopenia of unknown etiology is observed in most patients, and there is an increased risk of fractures to the long bones and vertebral bodies even in the absence of osteopenia. Vascular disease, including aneurysms, tortuosity of middle-sized arteries, and hypertension, is also frequently seen.
Diagnosis
The diagnosis of STAT3-HIES should be entertained in any child or young adult who has the above-described clinical picture or simply a history of recurrent infections. The hallmark laboratory finding is a marked elevation of serum IgE, almost always greater than 2500 IU/ mL. Levels can be as high as 150,000 IU/mL. Most patients also have peripheral eosinophilia. However, there is no correlation of clinical disease activity with the level of either IgE or peripheral eosinophilia. Atopic dermatitis is the major differential diagnosis because comparably high serum levels of IgE can be seen in patients in this disorder, as well as superficial skin infections. The severe and recurrent nature of the staphylococcal furuncles and pneumonias usually seen in HIES can help distinguish these patients from those with atopic dermatitis. Patients with other primary immunodeficiency syndromes may also manifest elevated IgE levels. Scoring criteria predictive of STAT3 mutations, including recurrent pneumonia, pathologic bone fractures, and lack of Th17 cells, are helpful.22 DNA testing of STAT3 should be used to make a definitive diagnosis; there are also rare patients who phenocopy STAT3-HIES but have mutations in pathway-related genes.
Therapy
The therapy for STAT3-HIES is largely supportive. Treatment emphasizes prevention of end-organ complications by using antimicrobial prophylaxis and aggressive treatment of infections. Prophylactic antibiotics (e.g., dicloxacillin or TMP-SMX) can be effective in pre venting S. aureus infections. Dermatitis can be treated with topical steroids. Bathing in diluted bleach can diminish colonization by S. aureus. Prophylactic antifungals can be helpful in patients with chronic mucocutaneous candidiasis. Intravenous antibiotics are used for deep seated infections or for resistant cutaneous infections. Surgical resection of persistent pneumatoceles is sometimes indicated to prevent superinfection by fungal and gram-negative organisms. Intravenous Ig infusions have shown some success in the management of HIES. Attention should also be paid to blood pressure and other vascular complications. Although a role for HSCT in STAT3-HIES is unclear, two children with STAT3 mutations who underwent transplantation for non-Hodgkin lymphoma are alive 10 and 14 years later with resolution of all immunologic and nonimmunologic features of HIES.
