Eosinophilia, Familial

Description

Familial eosinophilia is a rare autosomal dominant disorder characterized by peripheral hypereosinophilia (greater than 500 eosinophils/micro liter of blood) with or without other oragn involvement (summary by Rioux et al., 1998).

Clinical Features

Sparrevohn (1967) described an 18-month-old girl with recurrent asthmatic bronchitis, recurrent pulmonary infiltrates, leukocytosis, persistent marked eosinophilia with 'shift to the left,' intermittent thrombocytopenia, eosinophilia of liver and bone marrow, cellular infiltration including mast cells and eosinophils in skin and muscle, no signs of allergy by usual skin tests or of parasitism, and a chronic but benign course. The mother and a brother had transient eosinophilia and similar changes in skin and muscle biopsy. Zuelzer and Apt (1949) described the same syndrome in young children. One of their patients had a sister with marked eosinophilia.

In a 5-generation kindred with familial eosinophilia, Lin et al. (1997) identified 19 affected persons. Four subjects with sustained eosinophilia had documented cardiac involvement and 2 of them also had neurologic symptoms. Affected individuals had significantly higher white cell and absolute eosinophil counts, as well as lower red cell counts. Serum cytokine levels of interleukin-5 (IL5; 147850), interleukin-3 (IL3; 147740), and granulocyte-macrophage colony-stimulating factor (CSF2; 138960) and serology for parasitic helminth infection revealed no differences between the affected and unaffected individuals. No individuals studied had positive serology for parasitic infection.

Inheritance

Naiman et al. (1964) observed eosinophilia in 3 generations of a family. No allergies were recorded. Zeni et al. (1964) observed eosinophilia in 21 members of 3 generations of a kindred.

Using maximum likelihood analysis of variance components estimates in an Australian population-based sample of 232 Caucasian nuclear families, Palmer et al. (2000) found a narrow-sense heritability of blood eosinophil counts of 29.8%, i.e., additive genetic effects contributed just under one-third of the total variance. Increased blood eosinophil counts were closely associated with the presence of physician-diagnosed asthma. The study suggested the presence of important genetic determinants of the pathophysiologic traits associated with asthma. The authors proposed that blood eosinophil count is an appropriate phenotype for molecular investigations of the genetic susceptibility to asthma.

Mapping

Using polymorphic markers for a genomewide scan in a family with eosinophilia, Lin et al. (1997) and Rioux et al. (1998) demonstrated linkage to chromosome 5q. Multipoint analysis yielded a maximum lod score of 7.8 in the 5q31-q33 region (Lin et al., 1997). In the same family, Lin et al. (1998) found a pericentric inversion of chromosome 10, inv(10)(p11.2q21.2), in 2 of 8 affected persons who had peripheral blood or bone marrow karyotype analysis.

Molecular Genetics

Exclusion Studies

The region to which Rioux et al. (1998) mapped the EOS gene contains a cytokine gene cluster, which includes 3 genes whose products play important roles in the development and proliferation of eosinophils: IL3, IL5, and CSF2. Rioux et al. (1998) screened these 3 cytokine genes for potential disease-specific mutations by resequencing a subgroup of affected individuals from the large kindred. No functional sequence polymorphisms were found within the promoter, the exons, or the introns of any of these genes or within the IL3/CSF2 enhancer, suggesting that the primary defect in familial eosinophilia is not mutation in any one of these genes but, rather, in another gene in the area.