Renner ED, Puck JM, Holland SM, et al. J Pediatr. 2004;144:93–99
Purpose of the Study.
To describe the clinical and immunologic features of a distinct subgroup of patients with hyper-IgE syndrome (HIES) having autosomal recessive inheritance (AR-HIES) as distinct from the form having autosomal dominant inheritance (AD-HIES).
Thirteen patients from 6 families having AR-HIES and 68 of their relatives.
Patients were identified based on exhibiting a classic triad of features of HIES: recurrent skin abscesses, recurrent pneumonias, and elevated serum IgE. Medical records were reviewed, and patients and family members underwent uniform immunologic evaluations.
All families were consanguineous. Five are from Turkey and 1 is from Mexico. According to a previously developed scoring system (>20, HIES possible; >40, HIES highly likely), all 13 patients had scores ranging from 19 to >50. All relatives had scores of <20, supporting an autosomal recessive mode of inheritance. Eight of the 13 patients died between the ages of 6 months and 12 years. Features that are common to both forms of HIES include a chronic eczematous skin eruption with staphylococcal superinfection and upper and lower respiratory tract bacterial infections caused by common pathogens as well as unusual organisms (Proteus mirabilis, Pseudomonas aeruginosa, Cryptococcus neoformans) and chronic mucocutaneous candidiasis. Features that are found in AD-HIES that are not shared in AR-HIES include failure to shed primary dentition, bone fragility, coarse asymmetric facies, and pneumatocele formation. Features found only in AR-HIES include susceptibility to severe infection with molluscum contagiosum and herpesviruses. Patients with AR-HIES also have a high rate of life-threatening inflammatory cerebrovascular complications leading to stroke and/or hemorrhage. Serum IgE in patients with AR-HIES ranged from 4500 to 45 000 IU/mL (similar to AD-HIES). In general, serum immunoglobulin levels were elevated because of general stimulation resulting from infectious burden; specific antibody formation appeared normal. Eosinophil counts in patients with AR-HIES were from 2 500 to 18 000 cells per mm3, somewhat higher than in patients with AD-HIES. There were no major abnormalities of lymphocyte subpopulations, although in vitro T-cell responses to recall antigens and to a B-cell mitogen were depressed. Some patients with AD-HIES have impaired neutrophil chemotaxis and killing; this was not observed in those with AR-HIES. AD-HIES has been linked to a region on chromosome 4q. This linkage has not been observed in patients with AR-HIES.
AR-HIES is similar to but distinct from AD-HIES and most likely arises from an altogether different genetic basis.
HIES is among the earliest described syndromes of immunodeficiency, originally named Job’s syndrome because of the prominence of skin infections in the clinical phenotype. The genetic basis of this disease still eludes investigators. The description of an apparently distinct but very similar entity raises the exciting possibility that we may be seeing the results of defects in molecules that have a functional interaction in vivo. One may hope that defining the genetic bases of these diseases may lead to the same kinds of advances in our understanding of immune system biology, as have resulted from the study of other primary immunodeficiencies, with a potential for novel therapies.