Autosomal recessive hyperimmunoglobulin E syndrome: a distinct disease entity

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Abstract

Objective

The autosomal-dominant form of the hyperimmunoglobulin E syndrome (AD-HIES) has been described as a multisystem disorder including immune, skeletal, and dental abnormalities. Variants of AD-HIES are known but not well defined.

Methods

We evaluated 13 human immunodeficiency virus-seronegative patients from six consanguineous families with an autosomal-recessive form of hyperimmunoglobulin E syndrome (AR-HIES) and 68 of their relatives.

Results

Persons affected with AR-HIES presented with the classical immunologic findings of hyperimmunoglobulin E syndrome, including recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. In addition, severe recurrent fungal and viral infections with molluscum contagiosum, herpes zoster, and herpes simplex were noted. Autoimmunity was seen in two patients. Central nervous system sequelae, including hemiplegia, ischemic infarction, and subarachnoid hemorrhages, were common and contributed to high mortality. Notably, patients with AR-HIES did not have skeletal or dental abnormalities and did not develop pneumatoceles, as seen in AD-HIES. In lymphocyte proliferation assays, patients' cells responded poorly to mitogens and failed to proliferate in response to antigens, despite the presence of normal numbers of lymphocyte subpopulations.

Conclusion

The autosomal-recessive form of hyperimmunoglobulin E syndrome is a primary immunodeficiency with elevated immunoglobulin E, eosinophilia, vasculitis, autoimmunity, central nervous system symptoms, and high mortality. AR-HIES lacks several of the key findings of AD-HIES and therefore represents a different, previously unrecognized disease entity.

Section snippets

Methods

In six consanguineous families (Fig 1), 13 patients were suspected of having a primary immunodeficiency based on unusual, severe, recurrent infections (Table I) and eczematoid rashes. Laboratory screening demonstrated elevated serum IgE levels and pronounced eosinophilia (Table I). All patients >1 year old fulfilled the clinical triad of HIES consisting of recurrent skin abscesses, recurrent pneumonia, and elevated IgE levels. Detailed case reports of the families are published in the online

Genetics

The pedigrees of the six consanguineous families with AR-HIES are depicted in Figure 1. Four male and nine female patients were offspring of consanguineous matings; affected subjects were seen in only one generation of each family. Thus, the inheritance pattern is most consistent with an autosomal-recessive mode. Though not known to be related to each other, five families were from Turkey. Therefore, the origin of these families is of genetic interest. Figure 1 shows that families 2, 3, and 5

Discussion

We have defined a novel autosomal-recessive variant of HIES. AR-HIES can be separated from AD-HIES by four major criteria, and therefore represents a distinct disease entity. First, the inheritance pattern of HIES in the six consanguineous families is very likely to be autosomal-recessive. Second, AR-HIES has no connective tissue features. AR-HIES appears to be limited to immune and inflammatory abnormalities. Third, AR-HIES has a particularly high incidence of CNS complications, with

Acknowledgements

We thank Dr M. Uhl for review and interpretation of radiographic data and Dr M. Schlesier for interpretation of immunologic data.

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Supplementary data associated with this article can be found at doi:10.1016/S0022-3476(03)00449-9.

Supported by a grant of the Deutsche Forschungsgemeinschaft GR-1617/2, and the fellowship of the Immune Deficiency Foundation, Towson, Maryland (to B. G.).

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