An update on the hyper-IgE syndromes

The hyper-IgE syndromes (HIES; originally named Job's syndrome) are a collection of primary immunodeficiency syndromes resulting in elevated serum IgE levels and typified by recurrent staphylococcal skin abscesses, eczema and pulmonary infections. The disorder has autosomal dominant and recessive forms. Autosomal dominant HIES has been shown to be mainly due to STAT3 mutations and additionally results in connective tissue, skeletal, vascular and dental abnormalities. Autosomal recessive HIES has been shown to be mainly due to mutations in DOCK8; these patients are more prone to viral skin infections instead. This review article discusses the common clinical features of the syndrome, the genetic mutations responsible and the pathogenesis of the disease, as well as treatments currently used.


Introduction
Th e hyper-IgE recurrent infection syndromes (HIES) comprise a group of primary immunodefi ciency dis orders that exhibit markedly elevated IgE levels, recur rent staphylococcal skin abscesses, eczema and pulmonary infections. Both autosomal dominant and autosomal recessive forms of the disorder have been described. Most autosomal dominant HIES (AD-HIES) have been found to be due to mutations in STAT3 (Signal transducer and activator of transcription 3; MIM#147060), whereas DOCK8 (Dedicator of cytokinesis 8) mutations have been identifi ed in patients with autosomal recessive HIES (AR-HIES; MIM#243700). Patients with AD-HIES also exhibit distinct dental, skeletal and connective tissue abnormalities not found in patients with AR-HIES. Th e condition is thought to be rare, although the exact prevalence is unknown; approximately 200 cases have been described in the literature. STAT3 mutations have been found in many ethnic groups with an equal gender distribution.
'So went Satan forth from the presence of the LORD, and smote Job with sore boils from the sole of his foot unto his crown' Th e Book of Job, chapter 2, verse 7, Th e Bible, King James Version, 1611 Davis and colleagues fi rst described Job's syndrome in 1966 in their paper with two girls who had a triad of eczematoid dermatitis, and recurrent sinopulmonary and staphylococcal skin infections that distinctly lacked warmth, erythema or tenderness [1]. Subsequent to that, in 1972, Buckley and colleagues further characterised the syndrome, noting distinctive facial features and an elevation in IgE levels [2], thus leading to the use of the term Buckley's syndrome. Job's syndrome and Buckley's syndrome were subsequently found to represent the same disease [3], leading to its description as the hyper-IgE syndrome.
In 1999, the multi-system nature of HIES was further characterised by researchers at the NIH, who noted its autosomal dominant inheritance pattern [4]. Following this, in 2007, dominant-negative mutations in STAT3 were found to be responsible for the majority of cases of AD-HIES, thus linking the infectious and connective tissue disease abnormalities seen in the syndrome [5,6]. Subsequent research has resulted in a deeper understanding of the role of STAT3 in the pathogenesis and clinical features of the autosomal dominant form of the disease [7].
Th is review focuses mostly on AD-HIES, which occurs more frequently and is better described in the literature. Th e clinical features, genetics, pathophysiology and treatment of the condition are discussed in detail. AR-HIES is also touched upon, with reference to the similarities and diff erences compared to AD-HIES. In addition, other genetic diseases that also possess features of HIES are briefl y described.

Immunological and infectious features
Th e most frequently found immunological abnormalities are eczematoid rashes, skin abscesses, respiratory infection, marked elevation in serum IgE, mucocutaneous candidiasis and eosinophilia.
Th e rash is usually present within a few weeks of life and can be found at birth. It is typically a pustular or eczematoid eruption on the face and scalp [8,9], and histologically, eosinophils are detected. Th e rash can resolve or progress to become eczematoid dermatitis. Similar to conventional eczema, the rash is also driven by Staphylococcus aureus, and improves with Staphylococcus clearance measures.
Boils and furuncles are almost invariably found in AD-HIES and are often not associated with signs of infl ammation, resulting in the 'cold' abscesses in the original description of Job's syndrome [10].
Recurrent sinopulmonary infections represent another clinical hallmark in AD-HIES. Most patients have at least one episode of pneumonia, with more than 50% of patients having three or more episodes. Th e most common causative organism is S. aureus with Streptococcus pneumonia and Haemophilus infl uenzae less frequently implicated [4]. In addition, aberrant healing is frequently seen following pulmonary infection, with the development of pneumatoceles and bronchiectasis aff ecting up to 75% of patients. With the presence of parenchymal lung damage, the spectrum of pathogens then more closely resembles cystic fi brosis with Pseudomonas aeruginosa and non-tuberculous mycobacterial infection [11]. Th e pneumatoceles can also become occupied with moulds such as Aspergillus and Scedosporium [12]. Th e infection with Pseudomonas and moulds represents the major cause of mortality and morbidity in these patients [13]. Pneumocystis jiroveci infection has also been reported to occur in infancy prior to the development of bacterial lung disease [14,15].
Patients with AD-HIES also have increased susceptibility to fungal infection with up to 80% being aff ected with chronic mucocutaneous candidiasis. Focal  extra-pulmonary infections with Cryptococcus and Histoplasma have also been infrequently described [16,17].

Non-immunological features
Th e multi-system abnormalities seen in AD-HIES confi rm the widespread role played by STAT3 not only in the immune system, but also in the musculoskeletal, dental, craniofacial and vascular systems. Characteristic facial features have been noted in AD-HIES and start becoming apparent in late childhood and early adolescence; these fi ndings are almost universal by late adolescence. Th ere is an asymmetric facies with prominent forehead and chin, increased inter-alar width, wide-set eyes, coarse skin and a high arched palate [4,18]. Craniosyntosis and Chiari I malformations have also been reported, although these are largely asymptomatic and do not usually require surgical intervention [19][20][21].
Musculoskeletal abnormalities found in AD-HIES include minimal trauma fractures, osteopenia, scoliosis and joint hyperextensibility [4]. About half of patients with AD-HIES develop minimal trauma fractures, mostly aff ecting the long bones and ribs. Many patients also have osteopenia, although the correlation between fractures and osteopenia is not very strong. Sixty percent of patients have scoliosis, which can be severe enough to warrant surgical intervention. Joint hyperextensibility occurs in 68% of patients and may account for the earlier occurrence of degenerative joint disease in this group of patients.
Abnormalities in the dentition are frequently seen in AD-HIES with approximately 70% of patients having delayed exfoliation of three or more primary teeth. Reten tion of primary teeth is thought to be due to reduced resorption of tooth roots resulting in failure of eruption of permanent teeth, although the mechanism underlying this abnormality is not known [22]. Dental extraction of primary teeth usually results in normal eruption of the permanent dentition. Other oral cavity abnormalities have also been described, including a high arched palate, central ridges and fi ssures of the palate and deep grooves on the tongue and buccal mucosa with multiple fi ssures [23].
More recently, vascular abnormalities, including tortuosity, dilatation and aneurysms of middle sized arteries, as well as lacunar infarcts, have been identifi ed [13,19,[24][25][26]. Th e report of a man with coronary artery aneurysms resulting in myocardial infarction led to more systematic evaluation of the coronary arteries [24,27]. Coronary artery aneurysms and tortuosity are commonly seen in AD-HIES. Th ere was also an increased incidence of hypertension but not much atherosclerosis [28]. Cerebral artery aneurysms have also been reported and cerebral magnetic resonance imaging (MRI) has shown an increase in lacunar infarcts at a younger age as well as focal hyperintensities of indeterminate aetiology, although the clinical signifi cance of this is uncertain [19]. Th e aetiology of the vascular abnormalities in HIES remains to be elucidated, although it is suspected to be due to the eff ects of STAT3 on vascular remodelling resulting in arterial fragility, rather than an infl ammatory process. Murine data showing an increase in aneurysm severity and rupture after inhibition of STAT3 signalling or IL-17A blockade further supports this [26]. Dysregulation of transforming growth factor-β and matrix metalloproteinases are thought to be involved, although this remains to be proven [26,28].
Patients with AD-HIES have a higher incidence of malignant disease, particularly non-Hodgkin's lymphoma [29][30][31]. Other malignancies reported include Hodgkin's lymphoma [31], and single case reports of squamous cell carcinoma of the vulva (related to human papilloma virus infection) [32] and pulmonary adenocarcinoma with liver, bone and spinal cord metastases [33]. It should be noted that in the majority of reported cases of malignancy, a molecular diagnosis of a STAT3 mutation was not made and other genetic mutations might have been responsible for the syndrome [31]. Th e increased risk of malignancy is potentially due to both increased susceptibility to infection (resulting in tumorigenesis) as well as aberrant function of STAT3, which has been shown to have roles in tumour development [31]. Autoimmune disease, including systemic lupus erythematosus, vasculitis, dermatomyositis and membranoproliferative glomeru lo nephritis, have also been described but only occur infrequently [34][35][36][37][38].

Laboratory fi ndings
In keeping with the syndrome, marked elevations in serum IgE are usually present, with a serum IgE of >2,000 IU/ml being set as an arbitrary diagnostic level. However, as IgE levels only start to increase after birth, it is possible that the diagnostic threshold of >2,000 IU/ml may not be present in the very young. In addition, IgE levels may normalize or decrease in adulthood [4]. Using an age-adjusted value of ten times the age-appropriate level has been suggested in aff ected infants. Th e specifi city of the IgE remains uncertain as well. Elevated anti-S. aureus and anti-Candida albicans IgE levels have been noted, but there is no known relationship with disease severity [39].
Eosinophilia is present in >90% of patients, and does not correlate with the elevation in IgE. White cell counts are usually within the normal range, although both elevation and chronic leukopenia with neutropenia have been reported [40]. Reduced levels of CD45RO + central memory T cells and CD27 + memory B cells have also been noted [41][42][43]. Th e reduction of central memory T cells was thought to correlate with decreased ability to control latent varicella zoster and Epstein-Barr virus infection, with reduced T-cell memory responses to both viruses [43]. However, the signifi cance of the reduction of memory B cells was unclear as there was no relationship between this and specifi c antibody production or infection history [42].

Genetics
Dominant negative mutations in STAT3 were identifi ed as the cause of AD-HIES in 2007 [5,6]. Mutations were found mostly in the SH2 and DNA binding domains of STAT3 and were mostly missense mutations resulting in single amino acid changes or short in-frame deletions [5,6,[44][45][46][47]. Despite the diff erent functions of the aff ected domains, there does not seem to be a signifi cant genotypephenotype correlation [48]. Th ere is, however, a slight increase in some of the non-immunological features in patients with SH2 mutations, including a high arched palate, widened inter-alar distance, upper respiratory tract infec tions and scoliosis [49]. It has been hypothesized that the increased frequency of upper respiratory tract infections might be due to anatomical, rather than immunological, diff erences.
Laboratory experiments have shown that mutated STAT3 exerts a dominant negative eff ect on wild-type STAT3 function. Th is is further supported by data showing that mice with a complete deletion of a single STAT3 allele are phenotypically normal. It should also be noted that STAT3 is necessary for in utero development as homozygous STAT3 knockout is embryologically lethal [50].

Pathogenesis
Th e identifi cation of STAT3 mutations being the cause of AD-HIES has resulted in greater understanding of its role in both the immunologic and non-immunologic features of the disease, although there is much that is still not well understood. In broad terms, AD-HIES is a disease of both excess and too little infl ammation, as evidenced by the fl orid purulence seen in pneumonias contrasted with the 'cold' abscesses.
STAT3 mutations result in failure of diff erentiation of Th 17 cells and subsequent failure of IL-17 secretion (Figure 2). Th is explains part of the increased susceptibility to infection seen in AD-HIES [44,47,51]. Th e susceptibility to mucocutaneous candidiasis due to defective IL-17 signalling has been shown in patients with autoantibodies to IL-17 as well as mutations in IL-17F or the IL-17 receptor [52][53][54]. Abnormal IL-17 signalling in mice is associated with both candida and extracellular bacterial infections [55,56].
Th 17 cells are known to also secrete IL-22, which is responsible for upregulating secretion of antimicrobial peptides like human beta defensins and CCL20 [57]. Th e production of these antimicrobial peptides from keratino cytes and lung epithelial cells (when stimulated by T cells) is reduced in AD-HIES patients [58]. Th ese cell types have a far greater dependence on Th 17 cytokines for their production of antibacterial peptides and chemokines, suggesting that the skin and lung infections in AD-HIES might be a result of defi cient Th 17 diff erentiation.
Craniosyntosis, delayed tooth eruption and supernumerary teeth have been shown to result from defi cient IL-11 signalling as a result of homozygous missense muta tions in IL-11RA (encoding interleukin 11 receptor, alpha) [59]. Th ese mutations were shown to disrupt the ability of IL-11R alpha to activate STAT3-mediated signal transduction, hence resulting in clinical features seen in STAT3 defi ciency.
In view of the abnormalities in tissue remodelling (evidenced by abnormal healing after pulmonary infection or surgery), matrix metalloproteinases (MMPs) have been investigated in patients with AD-HIES because of the role they play. STAT3 has been shown to have a role in the regulation of several MMPs [60][61][62]. In a study of 37 patients with AD-HIES, plasma MMP-8 and MMP-9 levels were found to be three times higher than in controls, in contrast to MMP-3 levels, which were only a third of those in the controls [63]. MMP-8 has been shown to be involved in acute lung infl ammation [64], MMP-9 is associated with abdominal aortic aneurysms [65,66] and MMP-3 has a role in angiogenesis and fi brolysis, suggesting that they may be signifi cant in the abnormalities seen in HIES.

Diagnosis
Based on the work done at the NIH, a HIES scoring system had originally been developed for genetic linkage studies [4,67]. AD-HIES was considered highly likely with a score of >40 and unlikely with a score of <20 points. A score between 20 and 40 gave an intermediate probability, and patients might have AD-HIES and could be followed over time to obtain more data, or could have another genetic form of HIES.
Th e most common diff erential diagnosis in a child with eczema and a signifi cantly elevated IgE level is atopic dermatitis. With the discovery of STAT3 mutations and the fi nding that Th 17 cells are reduced in this group of patients, further eff orts were made to determine if this feature could be used to help improve diagnosis of STAT3 mutations [48,68]. Th ese studies confi rmed that in larger groups of patients with STAT3 mutations, Th 17 cells were reduced and could potentially help with making the diagnosis. Further to this, an alternative scoring system (incorporating Th 17 counts) to distinguish patients with and without STAT3 mutations has been suggested [48]. Th is scoring system divided patients into three categories: possible, with an IgE >1,000 IU/ml plus a weighted score of >30 of recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic facies and high palate; probable, with these features and a lack of Th 17 cells or a defi nite family history of HIES; and defi nite, with these features and a dominant-negative heterozygous mutation in STAT3 [48].
However, testing for Th 17 levels is a specialized test and may not be easily available, in which case testing for the STAT3 genetic mutation may be easier to perform in routine clinical practice. Although the scoring system represents a useful means for screening patients for genetic testing for STAT3 mutations, clinicians should not be put off from pursuing a molecular diagnosis in an individual patient on the basis of the diagnostic scores alone as the features of HIES can accumulate with time and more aggressive treatment can prevent the development of classical complications with time [48].

Treatment
Th e principal goals of the management of HIES is aggressive treatment of infections and good skin care. As patients with HIES may lack the typical infl ammatory features of infection, taking a good history, careful physical examination and appropriate imaging are necessary to pick up infections early. Th e dermatitis in HIES is largely driven by ongoing infection, particularly S. aureus. Consequently, treatment of the skin includes bleach baths or chlorhexidine washes as well as prophylactic antibiotics (for example, cotrimoxazole, which targets S. aureus). Th e development of skin abscesses has reduced following the introduction of prophylactic antibiotics, although these sometimes require surgical intervention.
Th e other signifi cant infectious problem is fungal infections. Chronic mucocutaneous candidiasis frequently occurs in the form of onychomycosis, and oral/vaginal thrush. Oral antifungal agents (for example, fl uconazole) are generally eff ective in controlling the candidiasis, and if necessary, can be used for prophylaxis. In patients with fungal lung infections, anti-Aspergillus therapy (for example, itraconazole, voriconazole or posaconazole) can be used. Anti-Aspergillus prophylaxis is also considered in patients with pneumatoceles in view of the higher risk of developing fungal infection.
A further point of note is that the aberrant tissue healing following pulmonary infections can result in parenchymal abnormalities that allow colonisation with P. aeruginosa, fungal infections and non-tuberculous myco bacteria. Superinfection with these organisms represents the most challenging aspect of long-term management. Eradication of these organisms is diffi cult and the role of surgery for areas of parenchymal abnormality is uncertain. Pulmonary surgery appears to be associated with a greater risk of complications and should be carefully considered and only undertaken in a centre with particular experience in the disease.
Hypertension is often seen in HIES and should be treated aggressively due to the association with vascular abnormalities [28]. Defects in antibody production have also been reported in HIES, although these are variable [69]. Th ese variable responses make it diffi cult to make blanket recommendations for immunoglobulin replacement therapy. Th ere is also limited data suggesting improvement in some patients with high-dose immunoglobulin therapy [35,70], although some form of controlled trial is probably warranted. At present, it would seem reasonable to test vaccination responses and consider therapy in those who fail to respond.
Bone marrow transplantation has also been tried in AD-HIES, although its exact role remains to be clarifi ed. Th e fi rst patient transplanted was a 46 year old man with recurrent pneumonias who received a peripheral stem cell transplant for B cell lymphoma. However, he died 6 months following transplant with interstitial pneumonitis [71]. Subsequently, a second case involving a 7-yearold girl was reported [72]. She was transplanted to treat her severe HIES and her skin lesions improved. However, she developed recurrence of symptoms after 4 years. Her serum IgE also returned to pre-transplant levels. Interestingly, this occurred despite full donor engraftment in all lineages, suggesting that the reasons for recurrence may have been somatic or not just confi ned to the haematopoietic system.
More recently, two unrelated male children with sporadic STAT3 mutations were transplanted for highgrade non-Hodgkin's lymphoma [73]. At 10 and 14 years following transplantation, both patients were reported to be well with continued resolution of both immunological and non-immunological features. Of particular note, both osteoporosis and the characteristic facies improved following transplant. Th e successful transplant in these two individuals is signifi cant as this potentially represents a means of preventing the long-term complications of chronic lung disease, vascular aneurysms and brain lesions.

Autosomal recessive hyper-IgE syndrome
Renner and colleagues [74] described a cohort of 13 patients from 6 consanguineous families that had features consistent with a diagnosis of HIES, including recurrent pneumonia and abscesses, eczema, elevated serum IgE and eosinophilia. However, these patients were diff erent from those with AD-HIES in that they did not have the connective tissue and skeletal abnormalities typically seen, but had increased viral skin infection, more neurological symptoms and autoimmunity. Th e disease entity was designated as AR-HIES.
Subsequently, in 2009, mutations in the dedicator of cytokinesis-8 gene (DOCK8) were found to account for the majority of patients with AR-HIES [75,76]. Both homozygous and compound heterozygous mutations were reported and large deletions were frequent; and most of the individuals with DOCK8 mutations had absent or reduced levels of protein. DOCK8 belongs to the 11-member family of DOCK180 proteins, which are involved in cytoskeletal rearrangement allowing cell migration, adhesion and growth.
DOCK8 is a Cdc42-specifi c guanine nucleotide exchange factor (GEF) at the plasma membrane needed for spatial activation of Cdc42 at the leading edge of DCs during interstitial migration. Absence of DOCK8 results in failure of DC migration to lymph nodes and defective CD4+ T-cell priming [77]. In B cells, DOCK8 functions as an adaptor protein downstream of TLR9 and upstream of STAT3, driving B cell proliferation and immunoglobulin production [78]. DOCK8 defi ciency impacts long-term memory of B cells as well as of virusspecifi c CD8+ T cells [79][80][81], which might explain the susceptibility to bacterial and persistent viral infections.
Clinically, patients with DOCK8 defi ciency had features similar to AD-HIES, with elevated IgE levels, eosinophilia, eczema, recurrent sinopulmonary infections, staphylococcal skin abscesses, mucocutaneous candidiasis and increased frequency of malignant disease. Food allergies were also present in patients with DOCK8 defi ciency (unlike AD-HIES). However, the connective tissue and skeletal abnormalities present in AD-HIES, such as retained dentition, characteristic facies and minimal trauma fractures, were much less frequent in DOCK8 defi ciency. Notably, however, patients with DOCK8 defi ciency were highly susceptible to viral skin infections, including severe Molluscum contagiosum infec tion, warts, herpes zoster and recurrent herpes simplex infections. Th ere is higher mortality at a younger age in DOCK8 defi ciency, with death often occurring before the age of 20. Other unusual features described in single patients include sclerosing cholangitis and colitis, granulomatous soft tissue lesions, primary central nervous system lymphoma and fatal metastatic leiomyosarcoma [82].
Several diff erentiating laboratory features have also been described in DOCK8 defi ciency, compared to AD-HIES. Although both show elevated serum IgE levels and eosinophilia, patients with DOCK8 defi ciency have reduced serum IgM levels as well as lymphopenia, mainly due to reductions in T cells, although normal levels are seen in some patients. Serum IgG and IgA levels as well as specifi c antibody production are variable, and abnormal lymphocyte proliferative responses, particularly in the CD8 + T cell compartment, have been noted [82].

Treatment
Broad treatment strategies in AR-HIES are similar to those in AD-HIES with good skin care, appropriate treatment and prophylaxis of staphylococcal skin infections, and prophylactic antimicrobial therapy for sino pulmonary infections. Allergic disease and asthma are more common in AR-HIES and require conventional treatment with inhaled corticosteroids and antihistamines. Specifi c antibody production in AR-HIES can be variable (despite normal IgG levels) and replacement immunoglobulin therapy has been used with anecdotal improvement in respiratory tract infections. Viral skin infections have unfor tunately not improved with replacement immunoglobu lin therapy. Widespread molluscum and human papilloma virus infection has been diffi cult to treat -standard therapies with salicylic acid, cryotherapy and imiquimod have had limited success; interferonalpha has been used anecdotally with mixed results.
Haematopoeitic stem cell transplantation has been reported in DOCK8 defi ciency in 12 patients to date [82][83][84][85][86]. In all individuals, resolution of recurrent infections (particularly viral skin infections with molluscum) and eczema occurred, although one individual continued to suff er from food allergies. Improvement in IgE levels as well as resolution of vasculitis were also reported. Th ese initial results suggest that stem cell transplantation in AR-HIES may represent an excellent curative option given the high morbidity and mortality seen in the disease.

Other hyper-IgE syndromes
Several other defi ned single gene mutations have been described to result in syndromes with features of HIES as well as other abnormalities.
Mutations in Tyk2 (Tyrosine kinase 2; MIM#611521) were originally described in a single patient with AR-HIES who additionally suff ered from susceptibility to Bacille Calmette-Guérin and salmonella, features more commonly associated with defects in the interferongamma/IL-12 pathway [87]. However, a second patient with Tyk2 mutations has been described with atypical mycobacterial and viral infections but without the pyogenic infections normally seen in HIES, suggest ing that the occurrence of the HIES phenotype in Tyk2 defi ciency may depend on other genetic loci as well [88].
Other genetic syndromes with features of HIES reported include the coexistence of HIES and Dubowitz syndrome (postnatal growth retardation, microcephaly and characteristic facies) [89]; HIES and pentasomy X [90]; and HIES and Saethre-Chotzen syndrome (acrocephalo syndactyly, hypertelorism and ptosis due to mutations in TWIST) [91]. Th e common mechanisms between these syndromes and STAT3 and DOCK8 defi ciency remain undefi ned at present.

Conclusion
With the identifi cation of the molecular aetiologies of AD-HIES and AR-HIES, our understanding of these diseases and, in particular, the role of STAT3 and of DOCK8 in immune function has increased. In addition it would be expected that as time progresses, the role of these molecules in immune function as well as their contribution to the various non-immunologic features in HIES will be further delineated. Th is may shed further insight into common diseases like eczema, susceptibility to staphylococcal infection and idiopathic scoliosis. Furthermore, a better understanding of the STAT3 and DOCK8 pathways will also help in understanding the aetiology and pathogenesis in other, as yet undefi ned HIES syndromes.