Autosomal Dominant Hyper IgE Syndrome
Autosomal dominant hyperimmunoglobulin E syndrome (AD-HIES)(OMIM#147060), also known as Job’s syndrome, is a primary immunodeficiency characterized by elevated immunoglobulin E (IgE), eczema, infections, and multiple connective tissue, skeletal, and vascular abnormalities. First described in 1966 by Davis et al., it was initially characterized by the triad of eosinophilia, eczema, and recurrent skin and pulmonary infections (Davis et al. 1966). Shortly thereafter, in 1972, Buckley et al. recognized that an elevated IgE levels was a part of this clinical spectrum, giving rise to the name hyperimmunoglobulin E syndrome. Dominant-negative heterozygous mutations in signal transducer and activator of transcription 3 (STAT3) were identified in 2007 as the link between recurrent infections and connective tissue abnormalities (Holland et al. 2007; Minegishi et al. 2007). Many cases are sporadic, but when familial, all individuals who carry the mutations express disease manifestations. Gender preference is not seen, and disease-causing mutations have been found in all ethnic groups.
STAT3 has been shown to be essential for embryogenesis, as homozygous STAT3 knockout mice do not survive. The majority of disease-causing mutations occur in the SH2 or the DNA-binding domains and are either short in-frame deletions or missense mutations that result in normal STAT3 protein expression but decreased function. While there are no clear genotype-phenotype correlations, there is a modest increase in some of the non-immunologic features, like high palate, wide nose, and scoliosis, in those with mutations in the SH2 domain (Sowerwine et al. 2012).
STAT3 is expressed widely and mediates various pathways involved in wound healing, host defense, and vascular remodeling, consistent with its multi-system clinical phenotype. Multiple cytokines transduce signal using STAT3, including interleukin (IL)-6, IL-10, IL-11, IL-17, IL-21, IL-22, IL-23, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, cardiotrophin-like cytokine, and ciliary neurotrophic factor. One of the defining immunologic abnormalities in this disease is failure of Th17 cells to differentiate, leading to impaired upregulation of antimicrobial peptides at epithelial surfaces, which results in Candida and Staphylococcus aureus infections. Interestingly, impaired IL-11 signaling has been shown to cause craniosynostosis, delayed tooth eruption, and supernumerary teeth in three consanguineous families in Pakistan with IL-11R alpha mutations due to lack of STAT3 transduction.
STAT3 also plays an important role in the regulation of matrix metalloproteinases (MMPs), and as expected those with STAT3 deficiency have abnormal levels of MMP (Sowerwine et al. 2012). Such a defect in tissue remodeling likely explains the vascular aneurysms, poor lung healing after infection, and characteristic facial features with porous skin seen in this population.
Earlier diagnosis of AD-HIES through greater recognition of clinical phenotype and advanced genetic testing is allowing for implementation of preventative antimicrobial therapies prior to development of significant comorbidities and is significantly improving the quality of life and life span of those affected.
Immunologic and Infectious Complications
AD-HIES is characterized by eczematous rashes, skin abscesses, recurrent sinopulmonary infections, and mucocutaneous candidiasis. Pustular or eczematoid eruptions on the face and scalp typically begin in the first few weeks of life and persist frequently through the teenage years. Biopsies of such lesions are often characterized by eosinophilia. This eczematoid rash is often exacerbated by Staphylococcus aureus, and as such, control of eczema is typically most successful with topical or systemic anti-staphylococcal therapy. Recurrent skin infections starting in early childhood, usually S.aureus abscesses, can also be a common skin manifestation in this disease. While drainage from these lesions is purulent, other signs of inflammation are often absent. Whereas typical skin infections are characterized by warmth and erythema, these abscesses lack those features and are considered “cold” abscesses.
Recurrent pulmonary infections begin in the first several years of life and are predominantly caused by S. aureus, Streptococcus pneumoniae, and Haemophilus species. Much like the absence of typical inflammatory signs with abscess formation, the systemic signs that classically accompany lung infections are often diminished leading to delayed diagnosis. There may be absence of fever, a normal white blood cell count, and fairly normal inflammatory markers despite radiographic signs that demonstrate new lung infiltrate. However, despite a lack of systemic inflammation, local airway inflammation is present, and copious airway secretions are seen. Such pyogenic pneumonias typically respond well to antibiotic therapy; however, frequent delay in diagnosis often leads to infectious complications like empyema, pneumatocele formation, and bronchiectasis. Aberrant healing following lung infection likely explains the increased frequency of pneumatoceles and bronchiectasis.
While resection of pneumatocele is appealing, the abnormal healing that presumably led to the pneumatoceles can also cause complications post-surgery, and there is a high rate of complication such as bronchopleural fistulae (Freeman and Olivier 2016). Avoidance of surgery stems from the concern of impaired healing as well as the anesthetic risks due to impaired lung function in the late stages of the disease.
While the majority of pulmonary mold infections are seen in areas of pre-existing parenchymal damage, occasionally features of allergic bronchopulmonary aspergillosis (ABPA) are seen. Making this diagnosis in a syndrome defined by high IgE levels is complicated, as not surprisingly antigen-specific serologies may be falsely positive to many allergens. Diagnosis, therefore, must be made using typical radiographic findings in addition to clinical response to corticosteroids, antifungal therapy, and omalizumab treatment.
Mucocutaneous candidiasis can present as disease of the nails, oropharynx, esophagus, and vaginal mucosa. Opportunistic infections can also be seen in AD-HIES. Pneumocystis jiroveci pneumonia has been reported in infants as their first pneumonia. Endemic fungi can disseminate, and lead to gastrointestinal disease, such as with histoplasmosis and Cryptococcus, or meningitis, with Coccidioides and Cryptococcus.
Reactivation of viral infections, specifically VZV, has been observed in this population at significantly increased rates. Work by Siegel et al. found that nearly one third of AD-HIES patients had a history of herpes zoster, starting as early as the second decade of life. Rates of VZV reactivation were 6–20-fold higher than the rate of herpes zoster in the general population over the same decades of life. Similarly, rates of herpes zoster recurrence in AD-HIES were significantly higher than those of the general population. This impaired control of chronic viral infections is proposed to be due to the observed defect in central memory T cells seen in AD-HIES patients (Siegel et al. 2011).
Interestingly, despite the elevated total and antigen-specific IgE, those with loss of function STAT3 mutations are less susceptible to clinical food allergy and anaphylaxis compared to other highly atopic patients. Work by Hox et al. demonstrated STAT3 signaling is essential for mast cell mediator-induced vascular permeability and that this is impaired in patients with AD-HIES (Hox et al. 2016).
Similar to many other primary immunodeficiencies, there is an increased incidence of both Hodgkin’s and non-Hodgkin’s lymphoma. There does not seem to be any relationship with EBV infection and malignancy in this population (Yong et al. 2012). As STAT3 is an oncogene, the development of lymphoma is paradoxical, and further investigation is necessary to understand the mechanism of tumorigenesis in patients with loss of function STAT3 mutations.
What makes AD-HIES unique among many primary immunodeficiency disorders is the multi-system involvement with vascular, GI, and musculoskeletal manifestations. Characteristic facial features usually manifest during adolescence and are characterized by a prominent forehead and chin, deep-set eyes, a broad nose, and porous skin. Failure to shed primary teeth is common, and if not surgically removed prior to the emergence of secondary teeth, then dental crowding is seen. Other abnormalities of the oral cavity can be seen, including a high-arched palate, hard palate midline sagittal fibrotic thickening, deep grooves on the tongue, and buccal mucosa with multiple mucosal fissures (Sowerwine et al. 2012). An increased frequency of aphthous stomatitis is also seen during the teenage/early adolescent years (unpublished observations). Additionally, some degree of craniosynostosis is typically seen in the skull but does not usually require surgical correction.
Other musculoskeletal abnormalities include hyperextensible joints, scoliosis, minor trauma fractures, and osteopenia. Scoliosis is present in many patients and may be severe enough to warrant surgical correction. Interestingly, wound healing following orthopedic surgeries is not usually complicated, as it is for pulmonary surgery. Approximately half of all AD-HIES individuals have minimal trauma fractures, and many have osteopenia. However, there is no direct correlation between bone mineral density and propensity to fracture. The joints are typically hyperextensible, and this may be responsible for the significant arthritis seen at younger ages than in the general population. Degenerative cervical spine disease in the fourth and fifth decade of life can cause neurological deficits and may require surgical stabilization (Fig. 1b).
Vascular abnormalities have more recently been recognized and include aneurysms, dilation and tortuosity of middle-sized arteries, and lacunar infarcts. Reported arterial abnormalities in AD-HIES include coronary artery aneurysms, bilateral berry aneurysms of the carotids, and a middle cerebral artery mycotic aneurysm. Further investigation of vascular abnormalities in a large AD-HIES cohort using cardiac CT and MRI found that coronary artery aneurysms and tortuosity are a common feature of the disease. These radiologic findings occurred in 70% of AD-HIES patients compared to 21% of the control group, and 37% of AD-HIES patients had aneurysms versus 3% in the non-HIES group (Sowerwine et al. 2012; Yong et al. 2012). The coronary artery aneurysms have resulted in myocardial infarction in several individuals, and therefore screening in adults is warranted as antiplatelet therapies such as aspirin may be indicated to minimize the risk of clot forming within the aneurysm. An increased incidence of hypertension was also seen in the AD-HIES group. A subsequent investigation demonstrated that coronary vessel walls are significantly thicker in AD-HIES than in healthy subjects, indicative of atherosclerosis being present but not leading to narrowing. The enlarged coronary lumen in AD-HIES, compared to CAD patients, is suggestive that disordered tissue remodeling associated with STAT3 mutations is responsible for these findings (Abd-Elmoniem et al. 2017).
Central nervous system abnormalities are found on imaging of AD-HIES patients at an incidence much higher than the general population. Focal hyperintensities are seen on brain MRI in the majority of individuals with AD-HIES. These lesions are predominantly white matter hyperintensities (Fig. 1c). The incidence of these lesions does seem to increase in number with age, although patients with AD-HIES are found to have these focal hyperintensities at a much younger age than would be expected in the general population. Similar brain lesions are also frequently found as incidental findings in the elderly. In the elderly, the focal hyperintense lesions are indistinguishable from those found in AD-HIES patients, and they have been associated with increased blood pressure, smoking, previous silent strokes, and other vascular risk factors. However, the clinical significance of these lesions in AD-HIES patients remains unknown as they are usually not associated with neurologic abnormalities. They may represent focal areas of demyelination, and whether they are due to ischemia, infection, or poor astrocyte activity is still unknown (Sowerwine et al. 2012). Overall, cognitive functioning in AD-HIES patients who develop early onset of these white matter hyperintensities is intact. In fact, these patients in one study scored in the average to high average range. However, the development of focal brain lesions may be a risk factor for relative weakness in specific areas like visual-spatial skills and working memory. Additionally, Chiari 1 malformations have also been found in a higher incidence in AD-HIES patients, but generally have not required surgical correction.
The gastrointestinal manifestations in STAT3 deficiency are consistent with both the immune abnormalities and the connective tissue findings seen in this disorder. This includes infections of the GI tract with Candida and other endemic fungal organisms related to the impaired epithelial host immunity presumably. There is also overlap between patients with STAT3 deficiency and those with connective tissue disorders like Marfan’s and Ehlers-Danlos syndromes; specific to the GI tract, those findings include diagnoses like diverticula and perforation. One large cohort of patients with STAT3 deficiency were analyzed for type and frequency of GI disorders. Interestingly, 60% of these patients reported one or more GI symptoms with the most prevalent being gastroesophageal reflux disease (GERD) and dysphagia. Another predominant patient report was of food impaction, which is likely related to the increased incidence of chronic eosinophilic esophagitis (EoE) found in this cohort. Chronic EoE also likely contributed to the esophageal rings, linear furrows, diverticula, and upper esophageal strictures seen on endoscopy. Evidence of underlying GI dysmotility and colonic perforation was also reported, which is likely related to issues of abnormal connective tissue repair and impaired mucosal healing, as discussed above. It should be mentioned that this cohort of patients did not have an increased incidence of inflammatory bowel disease (IBD) as is seen with many other disorders of immune dysregulation (Arora et al. 2017). This is perhaps related to the absence of Th17 cells in STAT3-deficient patients, as increased IL-17 signaling has been observed in IBD.
Laboratory Findings/Diagnostic Testing
As indicated by the name of the syndrome, the most consistent laboratory finding is an elevated serum IgE level. The peak is typically greater than 2000 IU/mL, but the level tends to decrease or even normalize with increased age. The IgE level does not correlate with disease activity or severity. The complete blood count is typically normal, but aberrations in the white blood cells can be seen with a relative neutropenia. As previously mentioned, the white blood cell count often fails to increase in response to infection. Eosinophilia is also common. Serum IgG and IgM are usually normal, and serum IgA is normal or low. However, specific antibody responses can be impaired. Lymphocyte phenotyping often reveals diminished memory T and B cells and very low IL-17-producing T cells.
The main target of therapy for AD-HIES involves the prevention and treatment of infections. Since AD-HIES patients can lack the classic signs of infection, like fevers, chills, or rigors, a careful history, physical exam, and relevant imaging are important to initiate timely therapies.
Prophylactic antibiotics targeting S. aureus (e.g., trimethoprim/sulfamethoxazole) are useful to decrease the frequency of pyogenic pneumonia, with the goal of preventing the development of pneumatoceles and bronchiectasis. Control of skin disease, exacerbated by S. aureus, also is benefited by oral anti-staphylococcal therapy, along with topical antiseptics like dilute bleach baths or chlorhexidine washes. Recurrent abscesses are usually controlled with good skin care and anti-staphylococcal maintenance therapy. Oftentimes, however, despite even aggressive skin care and decolonization of bacteria on the skin, infections in the axilla and groin can persist.
Antifungal prophylaxis may be of help in AD-HIES patients with chronic or recurrent Candida infections like onychomycosis. Those who have evidence of mold colonization or infection of the lung should be treated with antifungal agents with activity against molds, such as posaconazole. Anti-Aspergillus prophylaxis should also be considered for any AD-HIES patient with pneumatoceles, as they are at higher risk for development of Aspergillus infections in these areas of parenchymal lung damage. In areas with endemic mycoses, antifungal prophylaxis such as fluconazole for Coccidioides or itraconazole for Histoplasma should be strongly considered.
The management of lung disease in the setting of chronic infection with parenchymal lung injury is difficult. Airway clearance techniques such as secretion clearance devices and nebulized hypertonic saline should be utilized as in other patients with bronchiectasis. However, the benefits that aggressive airway management can offer must be balanced by the increased risk of hemoptysis that some with AD-HIES face. Those most at risk for acute episodes of hemoptysis include those with extensive bronchiectasis, infected pneumatoceles, or mycetomas, likely from abnormal vasculature associated with chronic infection. In such cases, antimicrobial therapy should be optimized, and inhaled airway irritants should be withheld during acute episodes of hemoptysis. Patients should be counseled for when to seek emergent evaluation should hemoptysis occur. Also complicating the manner in which airway clearance is delivered is the increased risk for minimal trauma fractures, thus limiting the use of devices like the percussive vest (Freeman and Olivier 2016).
Immunoglobulin replacement, administered by either intravenous or subcutaneous routes, has also been shown to significantly decrease the incidence of sinopulmonary infections. Furthermore, many AD-HIES patients likely benefit from such treatment as this population has diminished memory B cells and specific antibody production with age. Prophylaxis combining oral antimicrobials and immunoglobulin replacement should be strongly considered in patients with recurrent pulmonary infections or parenchymal lung damage (Yong et al. 2012; Sowerwine et al. 2012).
Routine vaccination according to an age-appropriate schedule is recommended. The majority of patients are able to make antibodies in response to protein and polysaccharide-based vaccines. These vaccines are usually tolerated well, with the exception of the 23-valent pneumococcal vaccine in which fever and large areas of edema and erythema develop around the injection site, oftentimes requiring systemic steroids (unpublished observations). For this reason, avoidance of the 23-valent pneumococcal vaccine should be considered in this population.
Optimal therapy for GI disorders remains to be determined. Experience with the use of oral or topical corticosteroid therapy for EoE is limited in this population, and it is reasonable to be concerned about using such a therapy in these patients who are already prone to both infections and osteoporosis. The use of long-term acid suppression for GERD, with either proton-pump inhibitors (PPI) or H2 blockers, raises similar concerns.
The role of hematopoietic stem cell transplantation (HSCT) in AD-HIES is unclear, particularly as some of the disease manifestations are of non-hematopoietic origin. The first two reports of HSCT in AD-HIES patient were deemed failures; the first suffered from lymphoma and died in the posttransplant period, and the second reported recurrence of AD-HIES features 4 years posttransplant despite full donor engraftment (Sowerwine et al. 2012; Yong et al. 2012). However, more recent reports of transplantation in this patient population indicate that HSCT may be an important therapeutic option in patients with severe disease manifestations. Two children transplanted with high-grade non-Hodgkin’s lymphoma, subsequently found to have STAT3 mutations, were successfully transplanted with improvement in immunologic and non-immunologic features of their underlying disease. One would not expect resolution of non-immunologic features, but improvement in osteoporosis and resolution of characteristic facial features were noted (Goussetis et al. 2010). A recent report of two Japanese patients followed for more than 8 years posttransplant showed normalization of IL-17 and IgE levels, even in the one patient with persistently mixed chimerism studies. While overall frequency of infections and hospitalizations decreased substantially, both patients still suffered from pulmonary complications following HSCT (Yanagimachi et al. 2016). Such reports suggest that HSCT to correct immunological defects before severe complications arise may be of benefit for AD-HIES patients with frequent and severe infections.
In summary, AD-HIES is characterized by mutations in STAT3 which result in both immunologic defects leading to infection susceptibility, as well as somatic features involving connective and vascular tissues, the brain, the gastrointestinal tract, and the skeleton. Knowledge of the genetic basis for the disease and improving understanding of the pathogenesis are allowing for earlier diagnosis and initiation of antimicrobial therapies, particularly anti-staphylococcal, prior to developing troublesome skin infections or parenchymal lung damage. As recognition and control of infections are improving, these patients are living longer, and our focus must turn to better understanding somatic aliments like scoliosis, atherosclerosis, aneurysms, and osteoporosis.
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