Published online April 16, 2007
PEDIATRICS Vol. 119 No. 5 May 2007, pp. e1121-e1125 (doi:10.1542/peds.2006-2649)
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ARTICLE

Brain Abnormalities in Patients With Hyperimmunoglobulin E Syndrome

Alexandra F. Freeman, MDa, Christina J. Collura-Burke, DO, MPHb, Nicholas J. Patronas, MDc, Lidia Stana Ilcus, MDc, Dirk Darnell, MSNa, Joie Davis, APRN, APNGd, Jennifer M. Puck, MDe and Steven M. Holland, MDa

a National Institute of Allergy and Infectious Diseases
c Clinical Center
d National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
b Walter Reed Army Medical Center, Washington, DC
e Department of Pediatrics, University of California, San Francisco, California


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. Hyperimmunoglobulin E syndrome is a multisystem disorder with abnormalities of the immunologic, connective tissue, and skeletal tissue systems. Central nervous system abnormalities have not been considered a feature of hyperimmunoglobulin E syndrome. We aimed to determine whether central nervous system abnormalities detected on brain MRI exist in hyperimmunoglobulin E syndrome and to characterize any identified abnormalities.

PATIENTS AND METHODS. Fifty patients aged from 3 to 52 years (mean: 24 years) with established diagnoses of hyperimmunoglobulin E syndrome had MRI of the brain as part of an hyperimmunoglobulin E syndrome natural history protocol. Abnormalities were described, measured, counted, and mapped. Patient charts were reviewed for neurologic findings and blood pressure measurements.

RESULTS. Focal brain lesions exhibiting high signal intensities on flow-attenuated inversion recovery and on T2-weighted techniques were found in 35 of the 50 patients. The focal hyperintensities were predominantly in the white matter of the cerebral hemispheres, and the number ranged from 2 to >50. The hyperintensities occurred more frequently in adults than in children, and no association with elevated blood pressure was found. Five patients had lacunar infarctions. Chiari type 1 malformations were found in 9 of 50 patients. Two patients had infectious complications presenting on MRI as cerebritis in 1 patient and as a hemorrhagic infarct in the other; both were found on autopsy to be fungal. Neurologic abnormalities were present in 1 patient with a lacunar infarction, the 2 patients with infectious complications, and in 1 patient with a subarachnoid hemorrhage secondary to a berry aneurysm.

CONCLUSIONS. Central nervous system abnormalities are common in hyperimmunoglobulin E syndrome. Focal T2 hyperintensities, not appreciated previously, represent a prominent feature of this rare disease that may assist in diagnosis. The etiology and clinical implications of these abnormalities remain to be investigated.

Key Words: immunodeficiency • lacunar infarction • brain imaging • Chiari malformation • hyperintensities

Abbreviations: HIES—hyperimmunoglobulin E syndrome • CNS—central nervous system • TR—repetition time • TE—echo time • FLAIR—fluid-attenuated inversion recovery • NF1—neurofibromatosis type 1

Hyperimmunoglobulin E syndrome (HIES; or Job's syndrome) is a primary immunodeficiency characterized by recurrent skin and lung infections, eczema, and extreme elevations of serum immunoglobulin E.1–3 In addition to the immunologic abnormalities, there are connective tissue and morphologic abnormalities in many patients, including characteristic facies, scoliosis, joint hyperextensibility, retained primary dentition, craniosynostosis, osteopenia, and pathologic fractures.3–5 Family pedigrees may show an autosomal dominant pattern of inheritance with variable expressivity, but most cases are sporadic. A distinct autosomal recessive form of HIES lacks the skeletal and dental features.6

Central nervous system (CNS) abnormalities in patients with HIES have not been described frequently. In our previous review of 30 HIES patients, 3 had noninfectious vascular events in the central nervous system,3 including an occlusion of the central retinal artery, bilateral aneurysms at the internal carotid bifurcation, an ischemic stroke in the territory of the left middle cerebral artery, and another stroke in the left posterior inferior cerebellar artery. These events prompted a study of cerebral MRI findings in a larger cohort of HIES patients to assess the prevalence, extent, and nature of CNS abnormalities.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Fifty patients with HIES were evaluated under an institutional review board-approved natural history protocol at the Warren Grant Magnuson Clinical Center at the National Institutes of Health between 1998 and 2004. Study subjects were diagnosed with HIES by experienced clinicians, assisted by a diagnostic scoring system, in which a score of >40 is consistent with HIES, a score of 20 to 40 is indeterminate, and a score of <20 is not suggestive of HIES.7 Individuals were included in this study if the HIES score was >40 or >20 with a first-degree relative with a score >40.

We obtained brain MRI scans as a part of a prospective study of the natural history of HIES. We have also included in this analysis MRI studies obtained for clinical care before enrollment. Conventional T2-weighted (repetition time [TR]/echo time [TE]: 3500–4850 milliseconds/99–104 milliseconds) and T1-weighted (TR/TE: 400–450 milliseconds/8–15 milliseconds) images were obtained in a 1.5-T magnet. In all but 3 patients, a fluid-attenuated inversion recovery (FLAIR) scan was also obtained using the following imaging parameters: TR/TE: 10002 milliseconds/145–148 milliseconds, slice thickness of 5 mm, 22 mL field of view, and a matrix of 192 x 256. Postcontrast studies were performed in a subset of patients when needed for clinical management but were not included in this study. Twenty-seven of the 50 patients had >1 MRI scan with an interval of 2 to 6 years (mean: 4.5 years). A total of 133 MRI scans was evaluated.

Each study was reviewed by 1 neuroradiologist (Dr Patronas) and abnormalities recorded. The number of brain lesions found on FLAIR or on the T2-weighted scans was counted, and the size and location of each lesion in the brain parenchyma (white versus gray matter) was recorded. In patients with >1 study, changes in the number of lesions on subsequent scans were noted. Patients with downward displacement of the cerebellar tonsils were classified as Chiari type 1 malformation if the lower pole of the tonsils projected >4 mm below a line connecting the tip of the clivus to the occipital bone.

Charts were reviewed for blood pressure measurements and neurologic deficits. Three blood pressure measurements spanning ≥2 years were averaged for all of the patients ≥18 years, and ≥2 blood pressures spanning ≥2 years were averaged for patients <18 years old.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Fifty patients with HIES, 23 males and 27 females, had brain MRIs. Their ages ranged from 3 to 52 years (mean: 24 years). The HIES scores in this cohort of patients ranged from 29 to 100 (mean: 69). Four of the patients had HIES scores <40; 3 of these patients were <10 years old and, therefore, may have had less assigned points from the scoring system because they had less time to accumulate as many infections, fractures, and retained teeth, and the characteristic facial appearance may not have yet appeared.

Thirty-five (70%) of 50 patients had focal punctate lesions in the white matter, which demonstrated high signal intensity on FLAIR and on T2-weighted sequences (Fig 1 and Table 1). The majority of lesions involved the subcortical and deep white matter, whereas the periventricular white matter was relatively spared. The incidence of such hyperintensities was greater in adults than children, with 9 (47%) of 19 patients ≤18 years and 25 (81%) of 31 patients ≥19 years having focal hyperintensities (Fig 2). The youngest patient with focal hyperintensities was 4 years old. The number of lesions per patient ranged from 2 to >50. Distribution between males 16 (70%) of 23 and females 19 (70%) of 27 was the same. Distribution of HIES scores was 29 to 100 (mean: 71) for patients with hyperintensities and 31 to 87 (mean: 63) for those without.


Figure 1
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  		FIGURE 1 Axial FLAIR brain image of a T2-weighted axial brain MRI of a 34-year-old woman with HIES is shown. There are multiple focal hyperintense lesions scattered in the white matter of both cerebral hemispheres.

 

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  		TABLE 1 Characteristics of the Patients With and Without Focal Hyperintensities on Brain MRI

 

Figure 2
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  		FIGURE 2 The presence of focal hyperintensities on brain MRI by patient age is shown.

 
In the 27 patients who had >1 MRI scan, an increase of >3 lesions was observed in 6 (22%) of 27. The mean increase in the number of lesions was 11.5. The age of patients with an increase in the number of lesions ranged from 25 to 49 years (median: 31 years), whereas the age of the patients without a change in lesion number ranged from 3 to 52 years (median: 25 years). In no patient was there a decrease in the number of lesions on follow-up scans, and the location of the lesions remained stable over time.

In 10 (20% overall) of the 35 patients with white matter abnormalities, gray matter lesions were found. Five patients had punctate lesions, 2 in cortical gray matter and 3 in the basal ganglia. The other 5 patients had focal hyperintense lesions in the basal ganglia presenting as lacunar infarctions (Fig 3). Lacunar infarctions were noted at relatively young ages (32, 33, 37, 38, and 40 years; mean: 36 years). In 3 of these patients, the lacunar infarction was identified incidentally on the initial MRI scan in the absence of neurologic symptoms. In 2 patients, the infarct was new compared with previous scans. One was a 37-year-old man with acute onset of ataxia and ophthalmoplegia, whereas the other, a 33-year-old woman, was neurologically intact.


Figure 3
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  		FIGURE 3 Axial T2-weighted image of the brain in a 37-year-old man with HIES is shown. A lacunar infarction is identified in the left hypothalamus and adjacent thalamus (arrow).

 
For the 25 patients >18 years old, patients with brain lesions did not have more hypertension than those without brain lesions. The mean blood pressure for patients with brain lesions was 121/79 mmHg and for those without it was 132/79 mmHg. Thirty-two percent of patients (8 of 25) with focal brain lesions had diastolic blood pressures >80 mmHg, and 28% (3 of 25) had systolic pressures >130 mmHg, as compared with 33% of patients (2 of 6) without such lesions with diastolic pressures >80 mmHg and 67% of patients (4 of 6) with systolic pressures >130 mmHg.

Two patients had infectious complications identified on MRI and confirmed at autopsy. Fatal Scedosporium prolificans cerebritis developed in the setting of extensive Scedosporium bronchitis and pneumonia in a 24-year-old woman. A fatal mycotic aneurysm because of Aspergillus fumigatus developed in the setting of a modest pulmonary aspergilloma in a 29-year-old woman. The mycotic aneurysm developed in the left middle cerebral artery circulation and presented on MRI as a hemorrhagic infarct and clinically as acute loss of consciousness with seizures.

Nine (18%) of the 50 patients had type 1 Chiari malformations (Fig 4). Bilateral internal carotid bifurcation berry aneurysms with subarachnoid hemorrhage were found in 1 patient; a venous angioma of the frontal lobe was found in another patient; capillary telangiectasia of the pons was found in 1 patient; arachnoid cysts were found in 2 patients; and third ventricle colloid cyst was found in 1 patient. With the exception of the subarachnoid hemorrhage complicating the berry aneurysms, all of these findings were incidental abnormalities in individuals without neurologic abnormalities.


Figure 4
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  		FIGURE 4 Sagittal T1-weighted image of the brain is shown. There is downward displacement of the cerebellar tonsils below the level of the foramen magnum (arrow). This constitutes a Chiari type 1 malformation. There was no associated syrinx in the cord.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
HIES is a multisystem disorder with abnormalities of the immunologic, connective tissue, and skeletal systems.3,5 There are few previous reports of CNS abnormalities in sporadic or autosomal dominant HIES, mostly related to infections.8,9 Recently, an autosomal recessive variant of HIES has been described that lacks many of the multisystem features of typical HIES but has a high incidence of severe viral infections, CNS vasculitis, and autoimmune abnormalities.6 The great majority of abnormalities that we found in autosomal dominant or sporadic HIES were without neurologic abnormalities, ranging from focal hyperintensities and Chiari 1 malformations to lacunar infarcts and CNS infections.

Focal hyperintense brain lesions were found in 70% of the patients, a rate much higher than the 0.5% rate in a study of 1000 healthy volunteers (mean age: 30.6 years; range: 3–83 years).10 Focal hyperintensities are also found as an incidental finding in the elderly and in neurofibromatosis type 1 (NF1).11–16 Focal brain hyperintense lesions are very common in elderly individuals, with a prevalence reaching >90% in some studies.11,15 These lesions are indistinguishable from the abnormalities encountered in our patients. In the elderly, the hyperintense lesions have been associated with increased blood pressures, evidence of previous silent stroke, smoking, and other vascular risk factors.15,17 They are known to represent manifestations of small vessel disease in various stages of evolution from perivascular edema secondary to ischemia at 1 end of the spectrum to lacunar or cortical ischemic infarction in the other. Published reports indicate that these lesions may be associated with cognitive decline.17,18 The white matter hyperintensities and cortical and deep gray matter lesions in our patients with HIES were found at ages much younger than would be expected in the general population, suggesting that there may be small vessel disease not recognized previously. Although we did not find significant differences in blood pressure between the HIES patients with and without focal brain lesions, the numbers are limited because of the rarity of HIES. Continuous ambulatory blood pressure monitoring may be indicated to observe a significant difference. Whether cognitive decline occurs in HIES, especially when there is an increase in lesion load over time, needs additional evaluation.

The hyperintensities described in NF1 seem very different from those in HIES and are likely of a different etiology. Hyperintensities in NF1 are typically located in deep gray structures (such as the basal ganglia), cerebellum, and the brainstem and occur more frequently in children than adults.12,13,16 The etiology of these lesions in NF1 remains unknown, although it has been hypothesized that they result from intramyelinic edema.19

Chiari 1 malformation was observed in 18% of HIES patients. There is limited information of the incidence of asymptomatic Chiari 1 malformation in the general population. However, in a retrospective study examining 22591 brain MRIs, Chiari 1 malformation (defined as >5 mm of tonsillar herniation below the foramen magnum) was found in only 165 studies (0.77%).20 Although their criteria were more stringent than ours in defining the degree of herniation (5 mm of tonsillar herniation versus 4 mm), the percentage of patients that we observed with tonsillar herniation significantly exceeded theirs. Because Chiari 1 malformation may be associated with syrinx, careful neurologic histories and examinations are necessary.

The finding of disseminated fungal infection to the brain in 2 patients emphasizes that fungal pulmonary infections, generally superinfections of pneumatocele cavities, in these patients need to be aggressively treated. Screening with brain MRI may be indicated in patients with pulmonary fungal disease even in the absence of any neurologic changes. Patients with HIES are typically thought to suffer from recurrent bacterial infections. Fungal infections, with the exception of mucocutaneous candidiasis, are infrequent.3 However, fungal opportunists, such as aspergillus, that colonize pneumatoceles that result from bacterial pneumonias can become invasive, as is evident in these 2 cases.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
CNS abnormalities on brain MRI are a remarkably common and previously unrecognized aspect of HIES. Several patients with lacunar infarcts in addition to focal hyperintensities suggest possible small vessel disease. Additional prospective neurologic and neuropsychologic evaluation is necessary to determine the clinical significance, if any, of these lesions in HIES. These newly recognized CNS abnormalities confirm the complex multisystem nature of HIES. These lesions are frequent enough in HIES and uncommon enough in the general population, especially at early ages, to be considered in future diagnostic classifications, and brain MRI may be useful in the diagnosis of uncertain cases.


   ACKNOWLEDGMENTS
 
This research was supported by the Intramural Research Programs of the National Institutes of Allergy and Infectious Diseases, the Clinical Center, and the National Human Genome Research Institute at the National Institutes of Health.


   FOOTNOTES
 
Accepted Nov 14, 2006.

Address correspondence to Steven M. Holland, MD, Building 10, CRC B3-4141, MSC 1684, Bethesda, MD 20892-1684. E-mail: smh{at}nih.gov

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

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  3. Grimbacher B, Holland SM, Gallin JI, et al. Hyper-IgE syndrome with recurrent infections-an autosomal dominant multisystem disorder. N Engl J Med. 1999;340 :692 –702[Abstract/Free Full Text]
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  6. Renner ED, Puck JM, Holland SM, et al. Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity. J Pediatr. 2004;144 :93 –99[CrossRef][ISI][Medline]
  7. Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999;65 :735 –744[CrossRef][ISI][Medline]
  8. Metin A, Uysal G, Guven A, Unlu A, Ozturk MH. Tuberculous brain abscess in a patient with hyper IgE syndrome. Pediatr Int. 2004;46 :97 –100[CrossRef][ISI][Medline]
  9. Garty BZ, Wolach B, Ashkenazi S, Weismart Y, Rachmel A, Nitzan M. Cryptococcal meningitis in a child with hyperimmunoglobulin E syndrome. Pediatr Allergy Immunol. 1995;6 :175 –177[ISI][Medline]
  10. Katzman GL, Dagher AP, Patronas NJ. Incidental findings on brain magnetic resonance imaging from 1000 asymptomatic volunteers. JAMA. 1999;282 :36 –39[Abstract/Free Full Text]
  11. deLeeuw F-E, deGroot JC, Achten E, et al. Prevalence of cerebral white matter lesions in elderly people: a population based magnetic resonance imaging study. The Rotterdam Scan Study. J Neurol Neurosurg Psychiatry. 2001;70 :9 –14[Abstract/Free Full Text]
  12. Itoh T, Magnaldi S, White RM, et al. Neurofibromatosis type 1: the evolution of deep gray and white matter MR abnormalities. Am J Neuroradiol. 1994;15 :1513 –1519[Abstract]
  13. Kraut MA, Gerring JP, Cooper KL, Thompson RE, Denckla MB, Kaufmann WE. Longitudinal evolution of unidentified bright objects in children with neurofibromatosis-1. Am J Med Genet. 2004;129A :113 –119
  14. Longstreth WT, Manolio TA, Arnold A, et al. Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. Stroke. 1996;27 :1274 –1282[Abstract/Free Full Text]
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