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Autosomal dominant hyperimmunoglobulin E syndrome

Autosomal dominant hyperimmunoglobulin E syndrome
Authors:
Attila Kumánovics, MD
Timothy R LaPine, MD
Harry R Hill, MD
Section Editor:
Jordan S Orange, MD, PhD
Deputy Editor:
Elizabeth TePas, MD, MS
Literature review current through: Jan 2023. | This topic last updated: Jun 29, 2022.

INTRODUCTION — A syndrome of recurrent staphylococcal abscesses, sinopulmonary infections, and severe eczema was described in 1966 in two red-haired females [1]. The condition was initially called "Job syndrome," based upon a description of the biblical character Job: "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" (Job 2:7). The cutaneous abscesses in patients with this disorder appeared "cold" (ie, lacking the typical signs of inflammation).

This disorder was later termed hyperimmunoglobulin E, recurrent infection syndrome (HIES) when an associated increase in serum levels of immunoglobulin E (IgE) was described [2,3]. Subsequent work revealed a broader array of clinical features and defined some of the functional defects in immune regulation in patients with classic autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES)/Job syndrome. Patients with this syndrome have characteristic facial features and skeletal findings and have recurrent infections (principally bacterial and Candida infections) and eczematous dermatitis [3-5]. In addition to elevated levels of serum IgE, there are abnormalities in the inflammatory process and associated immune regulatory defects. Autosomal recessive disorders with a somewhat similar presentation were identified.

This topic reviews the epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of AD-HIES. HIES-like disorders are discussed briefly here, and several are discussed in detail separately. (See "Combined immunodeficiencies", section on 'Phosphoglucomutase 3 deficiency' and "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency' and "Combined immunodeficiencies", section on 'Caspase recruitment domain-containing protein 11 deficiency'.)

EPIDEMIOLOGY — HIES is rare. The precise incidence is not known but is estimated to range from 1 in 500,000 to 1 in 100,000 [6-9]. It is found equally among males and females and is observed in members of succeeding generations. It has been reported in different populations and ethnicities.

GENETICS — Most patients with AD-HIES have a defect in signal transducer and activator of transcription 3 (STAT3), which is encoded on chromosome 17q21 (MIM #147060) [6-14]. The most common pathogenic variants reported are dominant-negative missense variants in the Src homology 2 (SH2) and DNA-binding domain (DBD) regions of STAT3 [6,7,10,11,15]. These pathogenic variants are described in both the sporadic and familial forms of AD-HIES. Larger in-frame amino acid deletions resulting in a truncated protein and pathogenic variants outside the DBD and SH2 domains have also been demonstrated [6,15], including noncoding (intronic) pathogenic variants [16]. Somatic mosaicism has been found in three patients with milder presentation [17-19]. STAT3 haploinsufficiency with nonsense mediated decay of the affected allele may cause a narrower spectrum of disease (elevated IgE, atopy, and locally invasive aspergillosis but no T helper cell type 17 [Th17] defect, recurrent bacterial infections, chronic mucocutaneous candidiasis, or connective tissue abnormalities) as reported in one patient [20].

Pathogenic variants in eight genes have now been identified that cause HIES-like disorders (see 'Differential diagnosis' below):

Tyrosine kinase 2 gene (TYK2), encoded on chromosome 19p13.2 (MIM #611521) [21,22].

Dedicator of cytokinesis 8 gene (DOCK8), encoding a protein implicated in the regulation of the actin cytoskeleton (MIM #243700).

Phosphoglucomutase 3 gene (PGM3), which encodes an enzyme in the biosynthesis of N-glucans (MIM #615816).

Zinc finger 341 gene (ZNF341), which encodes a transcriptional regulator of STAT3 expression (MIM #618282) [23].

Caspase-recruitment domain-containing protein 11 gene (CARD11) encodes a component of the nuclear factor kappa-B complex (MIM #607210).

ERBB2-interacting gene (ERBB2IP) encodes ERBIN, a STAT3-interacting protein [24].

Interleukin 6 receptor (IL6R) deficiency [25].

Interleukin 6 signal transducer gene (IL6ST) encodes protein critical for IL-6 and other cytokine signaling (MIM #600694).

Patients with HIES or HIES-like disorders who do not have an identified genetic defect may have defects in the regulatory elements of STAT3, DOCK8, or TYK2 or a novel gene defect further down the signaling pathway [26,27].

PATHOGENESIS — AD-HIES and related disorders are due to defects in the Janus activated kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway (figure 1) that is activated by cytokines, such as interleukin (IL) 6 and IL-2 [28-30]. Defects in the JAK-STAT pathway lead to impaired T helper cell type 17 (Th17) differentiation and function. The precise mechanisms that unify the infectious, dermatologic, skeletal, and immunologic aspects of this disorder remain uncharacterized [6-8,14].

STAT3 is a cytoplasmic protein and a component of the JAK-STAT pathway of signal transduction [31]. The binding of various cytokines to their receptors on the cell surface results in activation of JAK proteins, which in turn phosphorylate STAT proteins [32,33]. The STATs then form dimers, translocate to the nucleus, bind to specific sites on the DNA, and activate target genes. This mechanism of signal transduction is critical to the normal functioning of a wide array of cell types. STAT3 is important in the signaling induced by multiple families of cytokines, hormones, and growth factors, which is consistent with the multisystem defects seen in patients with HIES [10,11,34].

STAT3 defects lead to impaired Th17 function [28]. Defective Th17 differentiation and function (figure 2) is also seen in patients who do not have detectable STAT3 pathogenic variants [26]. An HIES-like disorder with a milder clinical phenotype was associated with a less severe defect in Candida albicans and Staphylococcus aureus-induced IL-17 production in one affected family [35]. Other defects that lead to impaired Th17 responses are discussed in detail separately. (See "Primary disorders of phagocyte number and/or function: An overview" and "Chronic mucocutaneous candidiasis".)

Susceptibility to infection is in part due to the defect in Th17 function, which results in decreased neutrophil proliferation and chemotaxis, decreased inflammation, and increased susceptibility to Candida and bacterial infections [3,4,7,36]. Keratinocytes and bronchial epithelial cells require stimulation with both Th17 and classic proinflammatory cytokines to produce antistaphylococcal factors, whereas other cell types only require the classic proinflammatory cytokines [37]. This may explain why staphylococcal infections are restricted to the skin and respiratory tract even though the defect in Th17 function is systemic. (See 'T cell defects' below.)

STAT3 defect also leads to impaired T helper cell type 9 (Th9) differentiation. Th9 cells produce IL-9, among others, and play a role in allergy, asthma, autoimmune inflammation, antitumor, and antihelmintic, protozoan, and other extracellular pathogen responses (figure 2). Decreased IL-9 secretion in HIES may contribute to the relative lack of allergy despite the enhanced IgE production in HIES [38].

Neutrophil chemotactic defects — Patients with HIES are not neutropenic, and their neutrophils engulf and kill bacteria normally. However, neutrophils demonstrate intermittent chemotactic defects in approximately 80 percent of patients [3,4,7,39-42]. In addition, in vitro and in vivo inflammatory cytokine production is impaired, and inflammation is minimal, leading to the characteristic cold (noninflamed) appearance of abscesses in some of these patients [1-3,7].

Defective Th17 cell production of IL-17 is involved in neutrophil chemotaxis and proliferation [7]. Thus, impaired neutrophil responses to the skin and lung infections may account for recurrent infections at these sites. Respiratory epithelial cells and keratinocytes are dependent upon IL-17 to produce antimicrobial peptides including those for antifungal responses. The abnormal IL-17 production probably also effects the pathways leading to interferon (IFN) gamma secretion in patients with AD-HIES since the mononuclear cells of these patients secrete decreased amounts of IFN-gamma upon stimulation [43,44]. Furthermore, in vitro incubation of neutrophils from HIES patients with IFN-gamma increased their chemotactic response [45], and a preliminary trial of subcutaneous IFN-gamma showed a decrease in pulmonary symptomatology and improvement in eczema [46]. Additional studies are underway in attempts to understand the relationship between IL-17 and IFN-gamma production in AD-HIES. (See 'Immunomodulating agents' below.)

T cell defects — STAT3 plays a crucial role in the differentiation of naïve T cells into IL-17 producing CD4+ T cells (Th17 cells) [47]. Th17 cells are involved in the response to fungal and extracellular bacterial infections. These cells are significantly reduced or absent in patients with HIES [15,47]. T cells from patients with HIES that were stimulated in vitro with staphylococcal enterotoxin B, C. albicans, or streptokinase failed to produce IL-17 [47]. (See "The adaptive cellular immune response: T cells and cytokines", section on 'Th17'.)

Other T cell defects have been reported, including deficient production of IFN-gamma and tumor necrosis factor (TNF) alpha [43,48], IL-9 [38,49], decreased numbers of CD8+ memory T cells [44], and diminished delayed-type hypersensitivity and lymphoproliferative responses to antigenic stimulation [50].

B cell defects and abnormal IgE regulation — The elevated levels of serum IgE in patients with HIES is probably an associated abnormality, rather than central to the pathogenesis of the disorder. IgE synthesis is a complex process, and a defect in the regulation of its production could express itself anywhere along its pathway to synthesis. IgE regulation involves T cell stimulation, appropriate cytokine production, and the ability of B cells to class switch toward the production of IgE.

Th2 cytokines, such as IL-4 and IL-13, enhance IgE production, while the T helper cell type 1 (Th1) cytokines, including IFN-gamma, IL-12, and IL-18, normally suppress it. Thus, defects in IFN-gamma production or secretion could contribute to the elevated levels of IgE observed [46], although one study demonstrated elevated IgE levels in mice with B cell-specific STAT3 deficiency, suggesting that aberrant immunoglobulin class switching to IgE is B cell intrinsic [51]. IL-21 is a negative regulator of class-switching to IgE. The increased IgE production in HIES due to STAT3 pathogenic variants may result from defective IL-21 receptor STAT3 signaling in B cells [52].

Analysis of B cell subpopulations in patients with HIES showed a reduction in memory B cells, and a vaccination study demonstrated a decreased response to a T cell-dependent antigen [53,54]. Increased plasma B cell-activating factor (BAFF) levels and reduction in BAFF receptor (BAFF-R) expression were also seen in HIES [54], similar to patients with common variable immunodeficiency [55]. Deficient humoral response may contribute to the decreased clearance of S. aureus in HIES patients [56]. These studies indicate the presence of both B cell-intrinsic and extrinsic defects in the humoral immunity of HIES patients, the true significance of which is unknown.

CLINICAL MANIFESTATIONS — HIES is characterized clinically by dermatitis and recurrent infections (principally bacterial sinopulmonary and skin infections), although there is significant variation in the constellation of symptoms and signs among individual patients [9,17,34,57]. Rates of food allergy and anaphylaxis are significantly lower in patients with HIES compared with patients with atopic dermatitis and similarly elevated IgE levels (food allergy 38 versus 58 percent and food-induced anaphylaxis 8 versus 33 percent, respectively) [58].

The clinical manifestations reported in 85 patients entered in the United States Immunodeficiency Network (USIDNET) Registry included [59]:

Skin abscesses (74 percent)

Eczema (58 percent)

Other allergic diseases (drug allergy 43 percent, food allergy 38 percent, environmental allergy 18 percent)

Retained primary teeth (41 percent)

Fractures (39 percent)

Scoliosis (34 percent)

Cancer (7 percent)

Skin manifestations — Skin manifestations are the most obvious clinical finding in HIES. These begin within the first few weeks of life, with a papulopustular, often crusted, rash that begins on the face and scalp and spreads to the upper trunk/shoulders and buttocks [60]. This rash progresses to an eczematous, impetiginized, severely pruritic rash that is similar to atopic dermatitis (picture 1) [3,61,62]. The rash is diffusely distributed and may become lichenified. Patients usually lack other common atopic symptoms, such as wheezing, food allergies, hayfever, and other allergic manifestations or a family history of atopy [3]. Unfortunately, there are few genotype-phenotype correlations in STAT3 pathogenic variant-positive patients, and IgE levels do not appear to correlate with the risk of atopic symptoms in patients with HIES [14].

The intense pruritus of the dermatitis is attributed to the release of histamine from cutaneous mast cells in response to the presence of Candida and staphylococci in the skin [3]. This theory is supported by high serum concentrations of IgE specific for these two main microbial pathogens. Skin biopsy often shows a predominance of eosinophilic infiltrates.

Skin infections frequently begin in early infancy, including abscesses, furuncles, and cellulitis, frequently leading to lymphadenitis. Staphylococcal abscesses often develop on and around the face, neck, and scalp (picture 2) [63]. These abscesses may appear "cold" or lacking the classical signs and symptoms of inflammation, or, alternately, they may be erythematous, warm, and tender. The most common microorganisms infecting the skin in patients with HIES are S. aureus and C. albicans [1-4,39,64]. It is unclear why some abscesses are cold, lacking rubor and pain, while others in the same patient may be associated with erythema and pain. As mentioned, there are few genotype-phenotype associations [14].

Sinopulmonary and other infections — Patients with HIES may have significant infections yet remain afebrile and report feeling well [65]. This is probably due to impairment of inflammation and decreased inflammatory cytokine production [10]. Lung infections are the second most common way for AD-HIES to present after skin manifestations. The mean age at first infection was found to be 10.5 months (range of 0 to 180 months) in a French national survey [9].

Patients often have chronic upper-airway infections with persistent and/or recurrent episodes of sinusitis, suppurative otitis media, and mastoiditis, which may require surgical intervention. Pathogens implicated in these infections include S. aureus, C. albicans, Haemophilus influenzae, groups A and B streptococci, gram-negative pathogens such as Pseudomonas, and fungi.

Pulmonary infections, which are most commonly due to S. aureus, are recurrent and may be life threatening [9,59]. Opportunist pulmonary infections with Pneumocystis jirovecii and Aspergillus, Pseudomonas, and Nocardia spp have been reported [9,59,64,66,67]. Lung abscesses were reported in 19 percent in one series and were most commonly due to Pseudomonas aeruginosa or Aspergillus fumigatus infections [59]. Patients with AD-HIES are at risk of late-onset invasive pulmonary fungal disease [68].

Pneumonias are frequently complicated by bronchiectasis, bronchopleural fistulae, and pneumatoceles [63,69]. Pneumatoceles can become superinfected with Aspergillus or Pseudomonas spp [66]. Nontuberculous mycobacterial infections are also common in STAT3-deficient patients with HIES who have developed structural airway disease, such as bronchiectasis, nodules, and cavities [70]. (See 'Prognosis' below.)

Additional nonpulmonary opportunistic infections that may be seen in patients with sufficient immune impairment include:

Mucocutaneous candidiasis that affects the oral or vaginal mucosa. The nails often become dystrophic due to chronic infection with C. albicans (picture 3) [69].

Endemic mycoses [71-74]:

Cryptococcus infections, typically meningitis

Histoplasmosis infections, usually affecting the gastrointestinal system

Coccidioides meningitis

Skin infections are common and are discussed above. (See 'Skin manifestations' above.)

Facial features — Affected patients resemble each other more than they resemble members of their own family [5,64]. The most characteristic feature is an increased alar width (broad nasal base) and broad nasal bridge (picture 4) [5]. Other features include protrusion of the forehead (frontal bossing), wide outer canthal distances, and deep-set eyes [5]. The prominent forehead, lower lip, and broad nose can already be observed during infancy, but the doughy consistency of the skin takes two to five years to become noticeable on the face [3,5]. Dysmorphia tends to increase with age.

There is notable thickening of the soft tissues of the face, ears, and nose that gives the skin an appearance of doughy consistency that is often described as "coarse facies" (picture 5). These features are apparent in 80 to 100 percent of AD-HIES patients and become more pronounced with age, particularly postpuberty [5,64].

Skeletal abnormalities — Skeletal and dental abnormalities, as well as growth retardation, have been associated with HIES:

It is common for patients to retain the primary teeth, leading to two rows of teeth [75]. The primary teeth may require extraction. Abnormalities of the hard palate and dorsal tongue are also seen [76].

A high incidence of scoliosis and osteoporosis associated with minimal trauma fractures is seen, generally with increasing age, in STAT3-associated HIES [64,77,78]. These findings are associated with osteoclastogenesis and osteopenia in mice and humans [7]. Hyperextensible joints have also been reported [63,64].

Bone fractures are associated with minor trauma and can be recurrent. The long bones are most frequently affected. Osteopenia or osteoporosis is noted in the majority of patients [78,79], possibly due to cytokine-mediated bone resorption. The cytokine profile of HIES patients is similar to that of postmenopausal women [80]. Low radial bone, but not hip and spine, mineral density was associated with fractures in one study [78].

Increased risk of lymphoma — The incidence of non-Hodgkin lymphoma is increased in patients with HIES, although the degree of increased risk is not precisely known [81-84]. A review of the literature described 23 patients with HIES and lymphoma, of whom at least eight died directly from this complication [81]. Other malignancies have been reported sporadically. Single case reports of squamous cell carcinoma of the vulva following human papillomavirus (HPV) infection and pulmonary adenocarcinoma with liver, bone, and spinal cord metastases have been described [85,86]. (See 'Prognosis' below.)

Neurologic abnormalities — One series described focal T2-weighted hyperintensities, ranging in number from 2 to greater than 50 per patient, visible on magnetic resonance imaging (MRI) of the brain in 35 of 50 patients with HIES [87]. The etiology of these lesions is unknown. In another series, having ≥21 of these focal white matter hyperintensities compared with fewer was associated with poorer scores on tests of global cognitive skills, visual-perceptual skills, and working memory [88].

Vascular abnormalities — A systemic review suggests that vascular structural anomalies are a major clinical feature of HIES, although the exact prevalence of these abnormalities in HIES is unknown [89]. These abnormalities are seen in all subtypes of HIES but appear to be most common in patients with autosomal recessive HIES. Vascular abnormalities can be venous or arterial, congenital or acquired, and they can cause significant morbidity and mortality. They include aneurysms and pseudoaneurysms. Abnormalities of the coronary arteries in patients with HIES include tortuosity, ectatic dilation, and focal aneurysms [89,90].

LABORATORY FINDINGS — An elevated serum IgE level and peripheral eosinophilia are the most common laboratory findings in patients with HIES [2,3,9,63,69,91,92]. However, these findings are associated with many other clinical conditions (table 1 and table 2) and are not diagnostic of HIES in the absence of typical clinical features. (See 'Clinical manifestations' above.)

Elevated serum IgE levels — Patients almost always have elevated serum levels of IgE [2,3,64,92]. Serum IgE levels generally range from 1000 to greater than 50,000 int. units/mL, with a mean serum level of 8384 kU/mL reported in one series [59]. A lower limit of 2000 int. units/mL is often used as an arbitrary cutoff for this syndrome. However, patients with HIES who have IgE levels as low as 400 int. units/mL with STAT3 pathogenic variants have been reported [13].

The serum IgE level is not related to the severity of disease. Even during infancy, patients will typically have elevated IgE levels [3]. The IgE level may remain stable or decline over time, becoming near normal in some adult patients with HIES. Anti-Staphylococcus and anti-Candida IgE titers usually remain elevated, however, and measurement of these may be useful in diagnosis, when available [91].

IgE in AD-HIES is largely not directed against allergens, and these patients do not usually have a significant history of immediate-type allergic disease, unlike patients with dedicator of cytokinesis 8 (DOCK8) deficiency, an autosomal recessive HIES-like disorder [93-95]. Overall, skin prick test results and clinical findings of allergy are in agreement with the specific IgE results in AD-HIES, and blood and skin test results are comparable with healthy individuals. (See 'Genetics' above and 'Dedicator of cytokinesis 8 and tyrosine kinase 2 deficiencies' below.)

Elevated eosinophil counts — Eosinophil counts frequently rise just prior to acute infection. Eosinophilia, up to 40 to 50 percent of the total white blood cell count, has been reported in some patients [59]. This level of eosinophilia usually exceeds that noted in atopic patients. Eosinophils have also been found in the sputum of patients with HIES during acute pneumonia [91]. (See "Approach to the patient with unexplained eosinophilia".)

Other findings — Routine laboratory evaluations used as screening tests for immunodeficiency disorders may reveal the following findings in patients with HIES:

Elevated immunoglobulin D (IgD) levels in some patients [45].

Decreased immunoglobulin G (IgG) subclass concentrations in some patients [96].

Poor response to both protein and polysaccharide immunizations in some patients [96,97].

Total hemolytic complement, C3, and C4 levels are normal [2]. Total white blood cell counts are normal in the absence of acute inflammation. Similarly, neutropenia or lymphopenia are not seen in the absence of infection.

There are no significant associations between bone metabolism studies (serum calcium, 25-hydroxyvitamin D, phosphorous, osteocalcin, intact parathyroid hormone, testosterone, and urine N-telopeptides of collagen and bone mineral density) and fractures in either adults or children [78].

DIAGNOSIS — The clinical diagnosis of HIES is based upon clinical and laboratory findings with confirmation of the diagnosis accomplished by identifying a genetic defect (eg, STAT3 pathogenic variant) by molecular testing [6,13]. The diagnosis is most commonly made in older children or adults with staphylococcal pneumonias or recurrent abscesses and chronic eczema. However, it can be made in infancy due to the presence of the distinct eczematous rash in a child with family members who are known to be affected (picture 1) [3]. A positive family history is common, with nearly half of patients in the United States Immunodeficiency Network (USIDNET) Registry reporting a family history of HIES [59]. Molecular testing is critical to confirm the diagnosis of the autosomal dominant form of HIES (AD-HIES).

A scoring system devised by the US National Institutes of Health (NIH) is available that can be used in patients with a family history of HIES (table 3). A score of 30 has a sensitivity of 87.5 percent and a specificity of 80.6 percent. The scoring system adjusts for age since some features are uncommon in infancy and early childhood. Some young children and even some adults with HIES, however, may not meet the scoring criteria. Thus, molecular screening should still be performed when there is a family history of HIES and the patient has some features suggestive of the disease, even if the score is <30.

Another set of diagnostic guidelines for STAT3-deficient HIES takes into account the total IgE level; T helper cell type 17 (Th17) cell count; five cardinal clinical features (recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic facies, and high palate) using the NIH scoring system cited above to determine the number of points for each (table 3); and family history [6]:

Possible – IgE >1000 int. units/mL plus a weighted score >30 of the five cardinal clinical features.

Probable – The "possible" criteria are met plus Th17 cells are low to absent or there is a family history of confirmed HIES.

Definitive – The "possible" criteria plus the presence of a STAT3 pathogenic variant.

The following also strongly suggest the diagnosis of STAT3-deficient HIES [93]:

Typical facies

Abscesses of internal organs

Severe infections

Pneumatoceles

Nail and mucocutaneous candidiasis

Scoliosis

Bone fractures

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HIES includes atopic dermatitis, Wiskott-Aldrich syndrome (WAS), severe combined immunodeficiency (SCID), and deficiencies in dedicator of cytokinesis 8 (DOCK8), phosphoglucomutase 3 (PGM3), tyrosine kinase 2 (TYK2), caspase-recruitment domain-containing protein 11 (CARD11), erb-b2 receptor tyrosine kinase 2 (ERBB2) interacting protein, and interleukin (IL) 6 signal transducer [82,98-101]. The differential diagnoses of elevated levels of IgE or eosinophil counts are reviewed above. (See 'Laboratory findings' above.)

Atopic dermatitis — A few patients with atopic dermatitis may also have extremely high IgE levels and recurrent superficial S. aureus skin infections and must therefore be distinguished from patients with HIES. (See "Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis".)

The range of serum IgE levels found in all patients with the syndrome of HIES does not significantly differ from that found in patients with severe atopic dermatitis [63]. The two disorders can usually be distinguished based upon the other infections and clinical features that are associated with HIES. Specifically, patients with severe atopic dermatitis may have superficial skin infections; however, they do not develop deep-seated abscesses or pneumonias, nor do they have bone fractures or abnormal facies.

Another difference between patients with atopic dermatitis and those with HIES is the antibody reactivity of their IgE. The IgE in patients with atopic dermatitis can have reactivity to a broad range of food and inhalant allergens and occasionally to S. aureus. By comparison, patients with HIES often demonstrate specific IgE and immediate skin test reactions to S. aureus and C. albicans, as well as to other bacterial and fungal antigens, in addition to inhalant and food allergens [63,102].

Wiskott-Aldrich syndrome — Patients with WAS also may have eczema and elevated levels of total IgE. However, WAS patients have thrombocytopenia, small platelets, and may exhibit bruising. In addition, abscesses are not common in patients with WAS. (See "Wiskott-Aldrich syndrome".)

Severe combined immunodeficiency — SCID may present with a desquamative skin rash, although this is usually distinguishable from the eczema of HIES. Some patients may also have elevated levels of IgE. Flow cytometry typically reveals significantly reduced T cell numbers in SCID. (See "Severe combined immunodeficiency (SCID): An overview".)

Dedicator of cytokinesis 8 and tyrosine kinase 2 deficiencies — Some patients with DOCK8 or TYK2 deficiency, which are combined immunodeficiencies, were previously thought to have autosomal recessive HIES due to similarities in presentation [21,22,28]. However, there are some differences in the clinical features. Newborn rash and coarse facies are clinical manifestations seen in HIES that are absent in DOCK8 deficiency. Hepatic disorders are seen in patients with DOCK8 deficiency but are not a clinical feature of HIES. In addition, higher rates of malignancy and mortality are seen in DOCK8 deficiency compared with HIES. Recurrent cutaneous viral infections are seen with both DOCK8 and TYK2 deficiencies but are not a common feature of HIES. Eczema and elevated IgE are variably found in patients with TYK2 deficiency. DOCK8 deficiency is reviewed in greater detail separately. (See "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency'.)

Phosphoglucomutase 3 deficiency — PGM3 deficiency causes a hyperimmunoglobulin E-like syndrome with glycosylation defects, although these patients lack the characteristic facies and chemotaxis defects [100,101]. A subset of these patients can have a more severe immunodeficiency and skeletal dysplasia [103]. PGM3 deficiency is discussed in greater detail separately. (See "Combined immunodeficiencies", section on 'Phosphoglucomutase 3 deficiency'.)

CARD11 loss-of-function pathogenic variants — Caspase-recruitment domain-containing protein 11 (CARD11) loss-of-function pathogenic variants can cause various phenotypes from SCID to combined immunodeficiency associated with atopy and elevated IgE levels or isolated severe atopy [104-106]. (See "Combined immunodeficiencies", section on 'Caspase recruitment domain-containing protein 11 deficiency'.)

ERBIN deficiency — ERBIN (encoded by the erbb2-interacting protein [ERBB2IP] gene) is a STAT3-interacting protein, and its deficiency leads to atopy, elevated IgE, joint hypermobility, and vascular abnormalities [24].

IL6R deficiency — Loss of the interleukin 6 receptor (IL6R) causes immunodeficiency, atopy, and abnormal inflammatory responses [25].

Interleukin 6 signal transducer (IL6ST) deficiency — IL6ST deficiency causes recurrent infections, eczema, bronchiectasis, elevated IgE, eosinophilia, impaired B cell memory and acute-phase response, as well as skeletal abnormalities [107,108].

MANAGEMENT — The management of the patient with HIES is difficult, principally because the pathophysiology of the immunodeficiency leading to infection has not been completely elucidated. In addition, treatment is based upon observational data and clinical experience since there are no randomized trials. Management of HIES requires a multidisciplinary team due to the multisystem aspects of the disease.

At present, the general management goals are the following:

Control the pruritus and eczematoid dermatitis.

Prevent the occurrence of severe systemic infections with early diagnosis and thorough treatment of localized infections or use of prophylactic antimicrobials.

Skin care — Management of the eczematoid dermatitis is similar to that for atopic dermatitis and consists of maintaining skin hydration and controlling the associated pruritus. Cutaneous lesions should also be examined closely for evidence of infection [7,69,109,110]. Antiseptic washes, such as dilute bleach baths or chlorhexidine, can be used to decrease S. aureus colonization. The use of oral cyclosporine and prednisone, topical calcineurin inhibitors, and phototherapy is contraindicated since these patients have impaired innate and adaptive immune responses. (See "Treatment of atopic dermatitis (eczema)", section on 'Maintaining skin hydration' and "Treatment of atopic dermatitis (eczema)", section on 'Controlling pruritus' and "Treatment of atopic dermatitis (eczema)" and "Treatment of atopic dermatitis (eczema)", section on 'Clinically uninfected skin'.)

Antimicrobial prophylaxis — The prophylactic administration of trimethoprim-sulfamethoxazole is useful in the prevention of cutaneous staphylococcal infections, including abscesses, as well as sinusitis, otitis media, and possibly pneumonia in patients with HIES, similar to in patients with chronic granulomatous disease [7]. The authors use trimethoprim-sulfamethoxazole prophylaxis in most patients with a history of severe and/or frequent infections. Dosing (based upon the trimethoprim component) is similar to that recommended for chronic granulomatous disease: 5 to 8 mg/kg/day of the trimethoprim component administered orally in two divided daily doses, or from 0 to 6 months, 120 mg/day; 6 months to 5 years, 240 mg/day; 6 to 12 years, 480 mg/day; and >12 years, 960 mg/day. Antimicrobial prophylaxis is continued as long as the patient continues to have skin, respiratory, or intestinal infections. Liver and kidney function and a complete blood count with differential should be monitored periodically. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Antibacterial prophylaxis' and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology" and "Methicillin-resistant Staphylococcus aureus infections in children: Epidemiology and clinical spectrum", section on 'Microbiologic characteristics'.)

Treatment of infections — Deep-seated bacterial infections should be aggressively managed using systemic antibiotics. Surgical drainage may be necessary, and the clinician should be vigilant for the development of osteomyelitis. Detection of pain in bones on direct pressure is suggestive of osteomyelitis and should be followed by appropriate radiographic studies to confirm and define the infection. Every effort should be made to isolate the infecting organism and determine its sensitivity. Methicillin-resistant S. aureus (MRSA) has become problematic in these patients. (See "Staphylococcus aureus in children: Overview of treatment of invasive infections", section on 'MRSA infections'.)

Oral and topical antifungal agents are beneficial for chronic mucocutaneous Candida infections [69,109,110]. Prophylactic regimens similar to those used in patients with human immunodeficiency virus (HIV) infection are employed. (See "Overview of prevention of opportunistic infections in patients with HIV".)

Control of pulmonary complications — Pulmonary complications include pulmonary insufficiency and pneumatoceles from repeated bacterial pneumonias. Patients can develop pulmonary compromise if multiple lobes are involved. Antibacterial prophylaxis is discussed above. The authors follow patients with persistent pneumatoceles using yearly pulmonary function studies and chest radiographs. Large, persistent pneumatoceles may require removal of segments of the lung or even lobectomy, although persistent large lesions have resulted in lobectomy only rarely in the authors' experience [7]. Complications from lung surgery are common and include prolonged bronchopleural fistulae [111]. (See 'Antimicrobial prophylaxis' above.)

Immunomodulating agents — Recombinant human interferon (IFN) gamma has been administered to a handful of patients with HIES, resulting in slightly lower IgE levels and decreased respiratory secretions and symptomatology [112,113]. However, a randomized, controlled trial has yet to be conducted, and these agents are not routinely used by most experts. In one of these reports, recombinant human IFN-gamma therapy was administered in doses similar to those used in chronic granulomatous disease (50 mcg/m2/three times per week subcutaneously) in patients with HIES and pulmonary infections [112]. Treated patients had fewer respiratory symptoms and secretions. IFN-gamma was also used in two patients with pulmonary aspergillosis while they were undergoing treatment that included lobectomy and antifungal medications. Therapy was continued until hospital discharge two to three weeks after surgery. Studies are underway to evaluate this cytokine and interleukin (IL) 17. (See 'Neutrophil chemotactic defects' above.)

The use of high-dose intravenous immune globulin (IVIG) has not consistently been shown to provide significant benefit to HIES patients, except in those with lowered immunoglobulin levels or significantly lowered vaccine responses to protein and/or polysaccharide antigens [109,110]. While some studies on the use of IVIG in AD-HIES have suggested benefit [114], other, better controlled studies have only shown minimal effect, primarily on eczema [115,116]. The authors do not use IVIG unless eczema is a major debilitating issue or lowered IgG or IgG subclasses and poor protein or polysaccharide vaccine responses are clearly documented in the face of worsening lung disease, because of the high costs of this therapy, potential harmful side effects, and inconvenience to the patients. A large, European, collaborative study indicated that some decrease in pulmonary infections and lung damage was probably the result of IVIG therapy [9].

Omalizumab, or anti-IgE, is a monoclonal antibody that blocks IgE-mediated histamine release from mast cells. It was developed for use in patients with severe asthma. The use of omalizumab in HIES patients should be approached with caution because of the extreme elevation of IgE in these patients. Omalizumab has been used successfully in a few patients [117]. Dupilumab, a human monoclonal antibody that blocks the alpha chain of the IL-4 receptor, was also successfully tried used to treat severe atopic dermatitis in one patient [118]. Further studies are needed.

Treatment of skeletal abnormalities — Treatment with bisphosphonates increases bone mineral density in HIES, but fracture prevention has not been shown in the small number of patients reported [77,78]. Bisphosphonate treatment had no effect on scoliosis progression in one patient with severe scoliosis [77]. Scoliosis may require surgical repair [64]. Differences between various bisphosphonate classes (see "Pharmacology of bisphosphonates") have not been evaluated, although the use of various drugs has been reported [119]. The use of calcium and vitamin D supplementation is reported, but the therapeutic effect is not known [77].

Treatment of dental abnormalities — Primary tooth exfoliation and permanent tooth eruption are delayed in a majority of patients with HIES due to unresorbed tooth roots. In a study of 13 patients with HIES, the permanent teeth erupted normally if retained primary teeth are extracted around the physiologic exfoliation age (after confirming the presence of the successor tooth by radiography) [120]. This helps avoid complications, such as impaction of permanent teeth within the jaw. Delayed wound healing was not observed in this study. Overall, careful oral hygiene should be emphasized.

Obstetric and gynecologic care — Gynecologic infections are commonly observed. In a study of 51 females from a French cohort, 12 percent had pelvic or breast infections [121]. In another chart review of 50 females from the US, 71 percent had gynecologic infections [122]. These included recurrent labio-perineal, breast, and vaginal abscesses, 40 percent of which required incision, drainage, and oral antibiotics [122]. This study also noted an increased risk of miscarriage, with 6 of 16 (38 percent) females reporting miscarriages and three (19 percent) reporting multiple miscarriages, significantly higher than approximately 1 percent for the general population. Pregnancy complications included prematurity, eczema flares, and lung disease progression. Over 30 percent of this cohort chose not to conceive to avoid having affected offspring or exacerbating underlying disease. Patients on oral contraceptives may be at increased risk of thromboembolic events due to the vascular abnormalities in HIES [122].

Transplantation — Early attempts of hematopoietic cell transplantation (HCT) for HIES did not demonstrate long-term benefits [123,124]. Subsequently, two patients with HIES with severe, recurrent pulmonary infections and non-Hodgkin lymphoma who underwent HCT with human leukocyte antigen (HLA) identical sibling donors showed sustained benefit over 10 and 14 years of follow-up [125]. No significant infections were reported after the immediate posttransplantation period. In addition, nonimmunologic manifestations of HIES resolved or did not develop. Further case studies suggest that HCT can improve immunologic parameters and reduce frequency and severity of infections. Nonhematologic organ defects are not corrected, although pulmonary complications may benefit from early immunologic correction before severe pulmonary complications occur [126,127].

PROGNOSIS — Infectious pulmonary complications appear to be the leading cause of death in patients with HIES, followed by lymphoma:

Pneumatoceles can become colonized with fungi and gram-negative bacteria, including A. fumigatus and P. aeruginosa [66,81,116]. Infected pneumatoceles can cause subsequent pneumonia, systemic infection, or sudden pulmonary hemorrhage. Vascular invasion by fungi may give rise to mycotic aneurysms with subsequent hemorrhagic complications in the lungs and other organs [81].

Lymphoma in patients with HIES has a relatively poor prognosis [81,82]. One patient with a history of HIES underwent a peripheral blood stem cell transplant for a B cell lymphoma [123]. This patient remained free of HIES-associated symptoms posttransplantation. However, he later died of pulmonary interstitial fibrosis related to the transplant.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Clinical manifestations – Hyperimmunoglobulin E recurrent infection syndrome (HIES) is characterized by recurrent skin and pulmonary infections (principally bacterial), and eczematous dermatitis (picture 1). Additional clinical manifestations seen in patients with autosomal dominant (AD) disease include coarse facial features (picture 4 and picture 5), failure or delay of shedding of primary teeth, recurrent fractures, hyperextensible joints, and scoliosis. There is significant variation in the constellation of symptoms and signs among individual patients. (See 'Clinical manifestations' above.)

Laboratory findings – Laboratory abnormalities include elevated total serum IgE levels, typically ranging from 1000 to >50,000 int. units/mL, and variable eosinophilia. (See 'Laboratory findings' above.)

Genetics and pathogenesis – Pathogenic variants in the gene encoding signal transducer and activator of transcription 3 (STAT3) cause autosomal dominant HIES (AD-HIES). STAT3 is important in the signaling induced by multiple families of cytokines, hormones, and growth factors, although the precise mechanisms that unify the infectious, dermatologic, skeletal, and immunologic features of this disorder are not yet known. (See 'Genetics' above and 'Pathogenesis' above.)

Diagnosis – The diagnosis of HIES is based upon the presence of suggestive clinical and laboratory findings (table 3) and is confirmed by molecular testing. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of HIES includes other inborn errors of immunity and disorders associated with elevated IgE (table 2) including atopic dermatitis, Wiskott-Aldrich syndrome (WAS), severe combined immunodeficiency (SCID), and deficiencies in dedicator of cytokinesis 8 (DOCK8), phosphoglucomutase 3 (PGM3), tyrosine kinase 2 (TYK2), caspase-recruitment domain-containing protein 11 (CARD11), ERBB2-interacting protein, interleukin (IL) 6 receptor (IL6R), and IL-6 signal transducer that lead to HIES-like disorders. (See 'Differential diagnosis' above and 'Genetics' above.)

Management – Management of patients with HIES is focused on skin care, prevention of infection, prompt and complete treatment of infections, and control of pulmonary complications. (See 'Management' above.)

We treat most patients with frequent and/or severe bacterial infections with prophylactic administration of trimethoprim-sulfamethoxazole. (See 'Antimicrobial prophylaxis' above.)

Significant bacterial and fungal infections should be aggressively managed with systemic antimicrobial agents, guided by culture and sensitivity data on the infecting organism. (See 'Treatment of infections' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to an earlier version of this topic review.

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Topic 3960 Version 28.0

References

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