Abstract
BackgroundX-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Cardinal symptoms are hypotrichosis, lack of teeth, and hypo- or anhidrosis, but the disease may also evoke other clinical problems. This study aimed at investigating the clinical course of XLHED in early childhood as the basis for an evaluation of the efficacy of potential treatments.Methods25 children (19 boys and 6 girls between 11 and 35 months of age) with genetically confirmed XLHED were enrolled in a long-term natural history study. Clinical data were collected both retrospectively using parent questionnaires and medical records (pregnancy, birth, infancy) and prospectively until the age of 60 months. General development, dentition, sweating ability, ocular, respiratory, and skin involvement were assessed by standardized clinical examination and yearly quantitative surveys.ResultsAll male subjects suffered from persistent anhidrosis and heat intolerance, although a few sweat ducts were detected in some patients. Sweating ability of girls with XLHED ranged from strongly reduced to almost normal. In the male subjects, 1–12 deciduous teeth erupted and 0–8 tooth germs of the permanent dentition became detectable. Tooth numbers were higher but variable in the female group. Most affected boys had no more than three if any Meibomian glands per eyelid, most girls had fewer than 10. Many male subjects developed additional, sometimes severe health issues, such as obstructive airway conditions, chronic eczema, or dry eye disease. Adverse events included various XLHED-related infections, unexplained fever, allergic reactions, and retardation of psychomotor development.ConclusionsThis first comprehensive study of the course of XLHED confirmed the early involvement of multiple organs, pointing to the need of early therapeutic intervention.
Highlights
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene ectodysplasin A gene (EDA) disrupting the prenatal development of ectodermal derivatives
A few rudimentary sweat pores could be detected in some boys (Table 1), anhidrosis was a common feature of all male subjects investigated in this study
Considering the prospective nature, the duration of this study, and the number of patients followed, our data will be relevant for regulatory agencies who evaluate outcomes from open-label drug trials in subjects with XLHED. This first comprehensive natural history study characterized the course of XLHED in male and female patients during the first five years of life, confirming the early involvement of multiple organs and pointing to the need of early therapeutic intervention
Summary
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by pathogenic variants of the gene EDA disrupting the prenatal development of ectodermal derivatives. Lack of teeth, and hypo- or anhidrosis, but the disease may evoke other clinical problems. The term ectodermal dysplasia (ED) refers to a heterogeneous group of rare congenital conditions affecting the normal development of ectodermal structures including skin, teeth, hair, nails, and eccrine glands [1]. X-linked hypohidrotic ectodermal dysplasia (XLHED; MIM #305100), the most common form of ED, is characterized by a clinical triad of hypotrichosis, hypo-, oligo- or anodontia, and hypo- or anhidrosis [2]. The lack of sweat glands may lead to life-threatening hyperthermia which is mainly observed in early childhood [3]. A certain single-nucleotide polymorphism (SNP) rs3827760 (c.1109T4C; p.Val370Ala) in the gene EDA1R, a gain-offunction allele associated with hair thickness and shovelshaped incisors that predominantly occurs in the Native American and East Asian population, was found to attenuate the severity of symptoms in at least one familial case of XLHED [11, 12]
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