A Family with a Novel Dominant Negative FOXN1 Heterozygous Variant of Uncertain Significance: A Case Report and Review of the Literature on the Clinical Course

Résumé fourni par la source

A 3-month-old male presented from Guatemala for a second opinion regarding an initial diagnosis of hyper IgE syndrome secondary to elevated IgE (50,000 IU/ml), eosinophilia (10 K/cu mm), and severe dermatitis complicated by staphylococcal abscesses. The patient had a history of early onset erythroderma, alopecia, and nail dystrophy. At our center, no thymic tissue was identified on ultrasound. He had a highly elevated CD4 T cell compartment (8,605 cells/µl), with a low fraction of naïve T cells (0.5%) with 98% Th2 skewing. His leading diagnosis was changed to Omenn syndrome. Subsequent genetic testing revealed a novel heterozygous variant of uncertain significance in FOXN1 (c.1444del and p.R482Gfs*68) that is predicted to have a dominant negative effect. The variant is also present in his father who has partial alopecia, nail dystrophy, and less than 5% T cells. Historically, heterozygous FOXN1 variants do not require definitive therapies such as thymic and/or bone marrow transplant due to reconstitution with age. Our patient has so far improved the naïve compartment of T cells to 9% now at 8 months of age. Nonetheless, recommendations for definitive therapies are less clear for our case, since dominant negative heterozygous variants can lower FOXN1 activity to less than 5% and immune reconstitution is delayed compared with other heterozygous variants. We reviewed the literature and through our collaborative network, we identified other dominant negative cases. Among these patients, one patient received a bone marrow transplant for severe T cell lymphopenia before the FOXN1 diagnosis was made.

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