H. Yavuz, Department of Pediatrics, Selçuk University, Faculty of Medicine, Konya, Turkey. E-mail: firstname.lastname@example.org
Autosomal recessive, autosomal dominant and the sporadic forms of hyperimmunoglobulin E syndrome (HIES) are multi-system disorders. Although HIES patients may present with cold abscesses, the vascular features of HIES are not well recognized. The objective of this review is to characterize the nature and spectrum of vascular abnormalities in HIES patients. Vascular abnormalities in HIES patients were reviewed with Medline and Google Scholar-based searches. In brief, the searches combined terms related to HIES with the terms related to vasculature. Furthermore, reference lists from the original studies and review papers identified were screened. There were vascular abnormalities in 25 patients with HIES. These abnormalities were identified as aneurysms (coronary, aortic, carotid and cerebral), pseudoaneurysms, congenital patent ductus venosus, superior vena cava syndrome, vasculitides, vascular ectasia, thrombosis and others. They may be congenital or acquired, in the veins and arteries, affecting both sexes. These abnormalities can be seen in all subtypes of HIES. They could be also fatal in children and adults. Limited pathological investigations revealed the presence of vasculitis. Three of the patients were found to have overlap diseases. In this review, the spectrum of vascular abnormalities in HIES are documented and discussed in detail for the first time. They highlight a previously under-recognized and potentially devastating complication of these disorders. These vascular abnormalities constitute one of the major clinical characteristics in HIES. The presence of hypereosinophilia, vasculitis and defective angiogenesis in HIES may contribute to the formation of vascular abnormalities in HIES.
Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent staphylococcal infections of skin and lungs and elevated levels of immunoglobulin E (IgE). Despite the presence of radiographic evidence of pneumonia or serious skin infections in these patients, they may be apyrexial and feel relatively well. This is caused by the lack of classical signs of acute inflammation, including warmth, hence the term ‘cold’ abscesses sometimes used to describe HIES. The majority of cases are sporadic; however, families with autosomal dominant (AD) or recessive (AR) traits have been described. AD-HIES is a multi-system disorder involving the connective tissue and skeletal systems, and presents with characteristic facies, wide nose, retained primary dentition, recurrent pathological fractures, scoliosis, hyperextensibility, craniosynostosis and ophthalmological features such as extensive xanthelasma, giant chalasia and strabism . Recently it was reported that de novo mutations in the signal transducer and activator of transcription 3 gene (STAT3) underlie the sporadic and dominant forms of HIES [2,3].
The characteristic systemic features of AR-HIES are autoimmune haemolytic anaemia, pericardial effusion and neurological symptoms, varying from facial paralysis to hemiplegia . One patient with AR-HIES had a mutation in the tyrosine kinase 2 gene (TYK2) .
There is now a growing body of evidence to support the vascular anomalies seen in HIES as a characteristic feature of the disease. Vascular anomalies have been noted in HIES from some of the descriptions made of the syndrome [5–9]. The spectrum of vascular features of HIES have not been recognized previously. The aim of this review is to determine the spectrum of vascular anomalies and related vascular events in individuals with HIES.
Materials and methods
This is a review of the literature; MEDLINE (to January 2009) and Google Scholar (to January 2009) were searched. In brief, the searches combined terms related to HIES and Job syndrome with terms related to vasculature (vasculitis, vascular abnormalities, aneurysm, vascular occlusion, vascular obstruction, vascular stenosis). Furthermore, reference lists from the original studies and review articles identified were screened. No limit was imposed regarding the language of publication.
A total of 20 papers were identified initially. These papers were classified as specific HIES papers, overlap syndromes and HIES variants.
Information about vascular abnormalities in patients with clear-cut HIES was found in 19 papers. They were reported as case reports [5–16], or with short paragraphs in related papers [17–23]. The 19 selected publications reported on a total of 25 participants; Tables 1, 2 and 3 summarize the characteristics of these patients. Patients from the 18th and 19th papers could not be included in the Tables due to insufficient information provided by the authors [22,23].
Table 1. The features of autosomal recessive hyperimmunoglobulin E syndrome (HIES) patients with vascular abnormalities.
Peak IgE (IU/ml)
Peak eosinophils/µl and (% of WBC)
Stated as U/ml.
‡ The % of white blood cell (WBC) information is unavailable. IgE, immunoglobulin E; U, unstated.
Clinical features that led to the identification of vascular abnormalities were cerebrovascular accidents, hemiplegia, cutaneous lesions, pneumatocele, foot swelling, chest pain and myocardial infarction [5,7,9–11,13,18]. Some findings were identified incidentally .
There were six AR-HIES patients with vascular abnormalities (Table 1). Five of the six cases were children (2–19 years); all children were female, and the female : male ratio was 5:1. Vascular abnormalities in these patients involved the brain and aorta. Aneurysms were reported in three patients (two aortic, one cerebral). One patient had variations in the calibre of the basal cerebral arteries. Another patient had an underperfusion of the large arteries and occlusion of the small vessels of brain, while one patient had leucocytoclastic vasculitis.
Vascular abnormalities were the cause of death in two AR-HIES patients , due to a ruptured cerebral aneurysm and a subarachnoid haemorrhage. An autopsy was performed on the patient who died of a ruptured cerebral aneurysm. Histology revealed a lymphocytic infiltrate instead of an eosinophilic infiltrate (as would be expected for an eosinophilic-type vasculitis in HIES). Renner et al. also reported another dead patient who suffered two cerebral vascular accidents. Autopsies of two further patients with AR-HIES who died from pneumonia were reported by Van der Meer et al.. Post mortem examination of the aorta of the first patient showed media necrosis, sclerosis and severe infiltration of the adventitial layer with plasmocytes, indicating the presence of aortitis. The aorta of the second patient had features of focal giant cell arteritis, including multi-nucleated giant cells, without signs of arteriosclerosis or mucinous degeneration. No microorganisms were identified in these two patients.
We also compared AR-HIES patients with and without vascular abnormalities for any differences in eosinophil and IgE levels in Renner et al.'s  series using the Mann–Whitney U-test. There were 13 patients in their series; their characteristics were delineated in the report. Four patients had vascular abnormalities . There was no statistically significant difference between the groups.
Five AD and three sporadic HIES patients were identified with vascular abnormalities (Table 2). Three of the eight were children; the age of one female patient was not mentioned. The female : male ratio was 5:3. In this group there were three patients with coronary aneurysms, one with aortic aneurysm, two with congenital patent ductus venosus, one with thrombosis of the left posterior inferior cerebellar artery and one with systemic lupus erythematosus (SLE) (overlapped), vasculitis and right parietal infarction. One of the AD-HIES patients died from a ruptured aortic aneurysm.
We also compared AD-HIES patients with and without vascular abnormalities for any differences in eosinophil and IgE levels in Grimbacher's  series using the Mann–Whitney U-test. There were 30 patients in their series; their characteristics were delineated in the report. Two patients had vascular abnormalities . There was no statistically significant difference found between the groups.
There were 11 HIES patients with vascular abnormalities whose genetic classification was unclear (Table 3). In this group there were two patients with pseudoaneurysm, three with vasculitis, three with aneurysms (coronary and aortic, carotid, middle cerebral artery), one with vascular ectasia and one with superior vena cava syndrome and jugular vein obstruction. Vascular abnormalities was unstated in one patient . Three of these patients were part of an autopsy series . All those who died were female adults. The vascular abnormality (vascular ectasia, aneurysm) of those patients who died were localized to the brain. One patient had thrombosis and aneurismal dilatation of cerebral artery with invading fungal elements within the artery lumen and infiltration the vessel wall. Three patients also had local vascular invasion by Aspergillus in the lung . Two patients had overlap syndromes with HIES [15,21]; they had systemic lupus erythematosus and Takayasu's arteritis.
Freeman et al. reported some patients with vascular abnormalities, but these were not included in this review because of insufficient information provided in the publication. One patient with bilateral berry aneurysms of the bifurcations of the internal carotid arteries and subarachnoid haemorrhage, five patients with lacunar infarctions in the basal ganglia, one patient with venous angioma of the frontal lobe and one patient with capillary telangiectasia of the pons were described in this group. Most of these findings were identified incidentally in individuals without neurological abnormalities .
Information on therapy was found in three papers [5,7,8]. Ling et al. treated their patients with aspirin and clopidogrel for coronary artery aneurysms. The patient reported by Van der Meer et al. refused surgical replacement for thoracic aorta aneurysm and was treated palliatively with metoprolol. Young et al. treated their patient, who had an aneurysm and thrombus of the coronary artery, with anti-coagulants and recanalization of the thrombus.
In 2004 Hay et al. reported five siblings who had chronic otitis or sinusitis, recurrent bacterial pneumonias, dermatitis and myoclonus. The oldest daughter died prior to evaluation of the family. In addition, the other siblings had cutaneous vasculitis and cognitive impairment. The IgE levels recorded ranged between 9400 and 43 000 IU/ml and eosinophils between 307 and 1386/µl. Magnetic resonance imaging (MRI) of the brain of one patient showed an old infarct. These patients appear to have some typical features of AR-HIES, except for myoclonus and cognitive impairment, and may be a variant of HIES.
We tried to search for any association between a certain type of vascular abnormality and a recognized feature of HIES (i.e. eosinophilia) in AR- and AD-HIES patients, but we could not find a distinctive relationship using the Kruskal–Wallis test.
This is the first review highlighting vascular anomalies in HIES patients which shows that vascular abnormalities may be seen in all types of HIES. They may be congenital or acquired, venous or arterial (Fig. 1). They may also be fatal in childhood and adulthood. The prevalence of vascular abnormalities in HIES is unknown; it is likely that the frequency of structural vascular anomalies in individuals with HIES is actually greater than reported here. Some of these findings were identified incidentally .
There are no specific diagnostic tests for HIES. A diagnosis of HIES relies upon identifying the presence of multiple non-specific signs that may develop over time. There are a few scoring systems that have been developed to help select patients for genetic testing ; however, the HIES scores are lacking in many of the published series and therefore the significance of how the HIES score relates to the vascular abnormalities seen in HIES patients remains unknown.
It is unknown if the pathogenetic mechanisms in all the cases are different or share a common aetiology. Eosinophilia is a prominent feature of HIES which may be encountered in all HIES types. The eosinophilia is more severe in AR-HIES patients than in AD-HIES patients, with values up to 17 500/µl (normal < 700) . Is there a role for eosinophils in these events? The reddish-orange granules of eosinophils include cationic proteins (major basic protein, eosinophilic cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase), cytokines and mediators. Major basic protein, eosinophilic cationic protein and eosinophil-derived neurotoxin are the primary mediators of eosinophil-associated toxicity to microbes and human tissue (as seen in eosinophilic myocarditis, pneumonitis, dermatitis, neuropathy and vasculitis). Target organ damage is unusual with mild eosinophilia, but its occurrence in association with moderate to severe eosinophilia (absolute eosinophil count > 1500/µl) does not appear to depend upon the specific cause of eosinophilia . The limited pathological studies [7,11,18] did not show eosinophilic infiltration in the tissue of HIES patients except in Shamberger's  case. Does the absence of eosinophilic infiltration exclude the role for eosinophilia? Can peripheral eosinophilia without tissue eosinophilic infiltration contribute to the development of vascular abnormalities?
A study of Kawasaki disease (KD) may help to shed some light on this . Coronary artery aneurysms or ectasia are the most important complications of KD, which is a systemic vasculitis. Terai et al. showed that 36% of patients with KD had eosinophilia before therapy. All patients with coronary artery aneurysms developed eosinophilia. The histopathology of early-stage KD involves perivasculitis and vasculitis of the microvessels. The arteritic process progresses to involve medium-sized muscular arteries such as coronary arteries. Eosinophils were more abundant in the microvascular lesions of coronary vessels in fatal cases, while in the aneurysm lesions of KD patients, eosinophils were less abundant than in microvascular lesions. Aneurysms with intimal proliferation reflect the vascular remodelling process of the damaged artery; therefore, the predominant cellular composition in aneurysms is likely to be different to microvascular lesions . Could this be a predominant mechanism in HIES?
Hypereosinophilia and eosinophilic infiltration of tissues are hallmarks of several important disorders, including parasitosis, allergic disorders and various myeloid diseases. This is also observed in vasculitic diseases such as Churg–Strauss syndrome and Wegener's granulomatosis . The literature suggests that perhaps a quarter of the patients with hypereosinophilic syndromes develop thromboembolic complications and that 5–10% of these were fatal . In addition, there are also reports that hypereosinophilic syndromes may be associated with radial, coronary, hepatic and ulnar artery aneurysms . Eosinophilic infiltrations have been implicated in the development of de novo coronary aneurysms. Furthermore, eosinophilic vasculitis with medial necrosis has been identified at autopsy in otherwise healthy individuals with spontaneous coronary dissection or rupture. It has therefore been proposed that cytotoxic substances released from perivascular eosinophils may result in direct medial destruction, predisposing to aneurysmal formation or spontaneous intimal dissection and sudden cardiac death .
As stated previously, patients with hypereosinophilic syndromes and vascular pathologies are mainly adults. This may suggest that the harmful effects of hypereosinophilia develop over a long period, or that these syndromes are more likely to affect older individuals. However, in our review some of the HIES patients are children; some congenital cases were also reported . This suggests that other mechanisms as well as hypereosinophilia may also play a role in causing vascular pathology. Here, a review of the different separate types of HIES may be useful.
AR cases. The pathology in these cases involves a vasculitic process [7,18]. It was suggested that the bacterial infections that are typical of HIES might be the aetiological factor for the vasculitic process. Bacteria may cause damage to vessel walls by activating coagulation and platelet aggregation, acting as antigens in immune complexes or as toxins directly damaging the endothelial cells . It was reported in one case that AR-HIES might be due to a mutation in the TYK2 gene . The exact role of TYK2 gene mutation in the pathogenesis of vascular injury is unknown.
AD and sporadic cases. AD-HIES is a multi-system disease that affects the skin, bone, teeth, lung and immune system; the relevant defects must therefore affect all these tissues. Some characteristics of these cases, such as aneurysm, skeletal involvement, hyperextensibility and craniosynostosis, also resemble Marfan's syndrome. It was suggested that pertubations of extracellular matrix homeostasis and/or remodelling caused by abnormal transforming growth factor (TGF)-β signalling was the main pathogenetic mechanism in Marfan's syndrome and related entities including the marfanoid–craniosynostosis syndromes [5,31]. However, abnormal TGF-β expression may also arise from the indigenous T cell defects found in HIES .
It was reported that dominant-negative mutations in STAT3 underlie sporadic and dominant forms of hyper-IgE syndrome [2,3], and AR-HIES might be due to mutation in the TYK2 gene . TYK2 is a non-receptor tyrosine kinase belonging to the Janus kinase (JAK) family. An array of cytokine signals are transduced by different combinations of JAK family kinases and STATs. When cytokines bind to their receptors, receptor-associated JAKs are activated to phosphorylate STATs, which in turn dimerize and translocate to the nucleus, where they activate target genes . The STAT3 protein directly regulates the vascular endothelial growth factor (VEGF) gene . VEGF is a potent, multi-functional, endothelial cell-specific growth factor. It stimulates proliferation and migration of endothelial cells. Dominant-negative mutations of STAT3 abolished the VEGF-induced nuclear translocation of phosphorylated STAT3 and inhibited human dermal microvascular endothelial cell migration completely . STAT3 and its phosphorylation are involved in the downstream signalling pathway of VEGF/VEGF receptor interaction and regulate VEGF-induced human dermal microvascular endothelial cell migration and tube formation . The congenital forms of vascular abnormalities associated with in the HIES series carried out by Sagiv-Friedgut et al. may be explained by the defective angiogenesis related to their STAT3 mutations. STAT3 is also required for embryogenesis . There is no information available on the presence of STAT3 mutations in patients with AD/sporadic-HIES in this review because many of our source articles pre-date the discovery of STAT3 mutations in HIES.
Unclassified cases. It was not possible to determine with certainty the genetic types of HIES in the unclassified patients due to insufficient information provided by the authors of these publications. It is possible that the case reported by Bardazzi  may be an AD-HIES. The limited pathological investigation performed also indicates the presence of vasculitis, as in AR-HIES patients. The post mortem study by Freeman  showed localized vascular invasion by Aspergillus.
Vascular aneurysms are a major feature of the vascular abnormalities seen in HIES. Atherosclerosis is not present in patients with aneurysm who did [7,18,20] and did not [5,9] undergo autopsies. As infections are common in HIES, it may have a contributory role in the formation of vascular abnormalities. In the report of a HIES patient who died from myocotic aneurysm caused by A. fumigatus, there is a clear association between infection and aneurysmal formation. . Inflammatory changes in aneurysms are the most common features at autopsy. However, there is no information in associated references that these inflammatory changes are related to infection [7,18,20]. The histopathological hallmark of myocotic aneurysm is the presence of infection and destruction of the wall of the vessel. Typically, myocotic aneurysms are multiple, distal and fusiform aneurysms, but the angiographic and clinical presentations can vary widely . For these reasons, we postulate that infection, eosinophilia and genetics alone or in combination be responsible for the development of vascular abnormalities in HIES.
We do not have clear data about the frequency of vascular abnormalities with HIES. The development of vascular abnormalities may be modified by ageing, which may then influence the overall frequency of these abnormalities. In addition, some vascular abnormalities may remain asymptomatic. However, two reports appear to suggest some ideas about the frequency of vascular abnormalities and that vascular abnormalities may be more common in AR-HIES [18,19]. Two of the 30 patients with AD-HIES in Grimbacher et al.'s  series had vascular abnormalities and vascular events. The first patient had an occlusion of the central retinal artery and a leaking berry aneurysm and bilateral aneurysms at the internal carotid bifurcations. The second patient had a thrombotic stroke of the left posterior inferior cerebellar artery. Four of the 13 patients with AR-HIES in Renner et al.'s  series had vascular abnormalities and vascular events (Table 1). In two cases the abnormalities were associated with fatalities. Additionally, the autopsy records of six patients with HIES revealed that three of them had vascular abnormalities (Table 3) . Recently, Freeman and Holland  reported the results of a frequency study regarding coronary artery anomalies, including arterial tortuosity, dilation and aneurysms in adult patients with AD-HIES. Of 18 individuals studied by either cardiac computerized tomography or MRI, 14 had one of these abnormalities, with tortuosity and dilation predominating and aneurysms being present in only four patients.
The findings in patients with HIES highlight a previously under-recognized and potentially devastating complication of this disorder. Vascular anomalies and their associated vascular events contribute to significant morbidity and mortality in HIES patients. Further studies are needed to determine the true prevalence of vascular abnormalities, their pathogenesis, prognosis and optimal therapy and to determine the need for preclinical screening. Given the data presented in this review, it would seem prudent to evaluate thoroughly all patients with HIES for vascular involvement, especially if there are presenting symptoms suggestive of vascular involvement (i.e. cerebral vascular accidents, cutaneous lesions, chest pain, etc.). These vascular abnormalities appear to represent a major characteristic of HIES.