Report of TSPEAR Variants, the Hypereosinophilic Syndrome, and Severe Atopy

Abstract

BackgroundBiallelic loss-of-function variants in the thrombospondintype laminin G domain and epilepsy-associated repeats (TSPEAR) gene have been associated with ectodermal dysplasia (ED), phenotypes that affect ectodermal-derived structures, including hair, skin, nails and tooth involvement, as well as hearing loss, specifically, sensorineural hearing loss. Historically, TSPEAR related disorders have been autosomal recessive. Other forms of ectodermal dysplasia including anhidrotic ectodermal dysplasia with immune deficiency (EDA-ID) have been associated with immune dysregulation, primary immunodeficiency, and atopy, including EoE, atopic dermatitis (AD), food allergy (FA), asthma, and allergic rhinitis (AR). The abnormal skin barrier and transepidermal allergen absorption has been proposed as a mechanism. We report the first known case of Hypereosinophilic Syndrome (HES) and severe atopy including eosinophilic esophagitis (EoE) associated with TSPEAR mutations.Case presentation: 5-year-old male with a history of FA, asthma, and AR who later developed HES, severe AD, and EoE. HES presented age 2-years, resolving with a course and taper of high dose prednisolone. Remarkable findings on HES evaluation included an absolute eosinophil count of 10,480, IgE of 2,566 IUnits/mL, and EoE with up to 60 eos/HPF in esophagus on EGD. He was multiply sensitized to environmental allergens. FISH analysis was normal with no evidence of FIP1L1/PDGFRA. Bone marrow biopsy was significant for a normocellular bone marrow with multilineage hematopoiesis and markedly increase in eosinophils. Genetics evaluation noted hypodontia, pointed teeth, and coarse hair. He was found on whole exome sequencing to have 2 variants of unknown significance (VUS) in TSPEAR gene, one from each parent. His presentation was felt to be feasibly related to the VUS but more information about the VUS was needed to provide molecular confirmation. ConclusionWe report the first known case of association of two VUS in the TSPEAR gene with immune dysregulation including HES and severe atopy (FA, asthma, AR, AD, and EoE). Epidermal abnormalities with TSPEAR mutations may be similar to other ED syndromes with regards to development of severe atopy and immune dysregulation, with transepidermal sensitization playing a role.