Hyper-IgE and recurrent infection syndrome (Job’s syndrome): a rare disease with common problems

Steven Holland

Author address: 

University of Berlin, Dept. of Hematology and Oncology, Augustenburger Platz 1, 13353 Berlin, Germany


Hyper-IgE syndrome (HIES) is a rare autosomal disorder characterized by recurrent infections, typically of the lower respiratory system and skin, eczema, extremely elevated levels of IgE, eosinophilia, and abnormalities of the connective tissue, skeleton, and dentition. The majority of patients have facial abnormalities including ocular hypertelorism, a prominent, protruding, triangular mandible, and a broad, somewhat bulbous nose. Failure of primary dental deciduation, leading either to failure of secondary dentition eruption or retention of both sets of teeth is common Many patients also have abnormalities of bone formation and metabolism, which may result in fractures, severe scoliosis, kyphosis and short stature, and craniosynostosis. HIES occurs spontaneously in all racial and ethnic groups, and in many cases is transmitted as an autosomal dominant trait. IgE is greatly elevated at some point in the life of patients with HIES. A few patients have been observed to drop their IgE levels below 2000 IU/ml as they get older and yet retain their high susceptibility to infection. Autosomal dominant transmission with variable penetrance is common. The rate of spontaneous occurrence is unknown, but sporadic cases account for at least half of those recognized so far. Genetic linkage to proximal 4q has been shown, but several families are not linked to 4q, suggesting that there are at least 2 genetically distinct types of autosomal dominant HIES. There may also be autosomal recessive forms of HIES. Therefore, HIES is likely a complex autosomal disorder with both dominant and recessive forms. Patients usually present within the first days to months of life with severe eczema, mucocutaneous candidiasis, and severe diaper rash. Sinus or pulmonary infections, predominantly with S. aureus or Hemophilus infiuenzae, are common. Post-inflammatory pneumatoceles are often noted early in life. Otitis media and externa are common. Infections occur less frequently in bone and joints, and very infrequently in liver, kidneys, and the gastrointestinal tract. Documented sepsis is rare. Deep tissue infections are frequently extensions of cutaneous or dental infections such as paronychia or apical abscesses. Other pathogens that have been recovered include Aspergillus species, Pseudomonas aeruginosa, Streptococcus pneumoniae, group A streptococci, Cryptococcus neoformans, and C. albicans. Although several patients have survived into adulthood and middle age, there is often severe pulmonary destruction. Cerebrovascular events (strokes, reversible ischemic neurological deficits, unidentified bright objects/T2 hyperintensities on MRI scanning, carotid artery aneurysms) have been seen in an unusually high number of patients. Frequent bony abnormalities are common in HIE. The frequency of pathologic fractures in the population reported by Grimbacher et al was 58%. Although the general mechanism for these abnormalities is unknown, Leung et al. have demonstrated increased in vitro bone resorption by monocytes from patients with HIE. The syndrome is defined by marked elevations of IgE (>2000 IU/ml), with levels of more than 50,000 IU/ml reported. White blood cell counts are typically in the normal range, but have been reported to range from 60,000 to 1700 per microliter. Mild to moderate eosinophilia is the rule, although occasional patients do not show this. There is no correlation between IgE levels and degree of eosinophilia or clinical disease. Mucocutaneous candidiasis with involvement of mouth, vagina, intertriginous areas, fingernails, and toenails affects about 50% of patients with HIE. High-dose prolonged intravenous antibiotics are required for eradication of infection. Empirical acute coverage should consider S. aureus, H. [email protected], and S. pneumoniae. The former two organisms account for the majority of acute infections. Colonization of pneumatoceles and bronchiectatic lung with Pseudomonas aeruginosa and Aspergillus species can be especially problematic. The role of prophylactic antibiotics has not been rigorously investigated in this setting but there is general consensus for their use. Most investigators direct coverage at S. aureus with a synthetic penicillin. A scoring system has been devised to aid in the formal diagnosis of HIE patients. Davis SD, Schaller J, Wedgewood RJ. Job’s syndrome. Recurrent, "œcold," staphylococcal abscesses. Lancet 1:1013, 1966. Buckley RH, Wray BB, Belmaker EZ. Extreme hyperimmunoglobulin E and undue susceptibility to infection. Pediatrics 49:59,1972. Donabedian H, Gallin JI. The hyperimmunoglobulin E recurrent infection (Job’s) syndrome: A review of the NIH experience and the literature. Medicine (Baltimore) f-2195, 1983. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O’Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections-an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692-702. Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4 Am J Hum Genet. 1999;65:735-44. Hutto JO, et al. Cryptococcosis of the colon resembling Crohn’s disease in a patient with the hyperimmunoglobulinemia E-recurrent infection (Job’s) syndrome. Gastroenterology 94:808,1988

abstract No: 


Full conference title: 

12th International Symposium on Infections in the Immunocompromised Host
    • ISIIH 12th