Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Loschgestr. 15, 91054, Erlangen, Germany.
FDNA Inc, Boston, MA, USA.
Orphanet J Rare Dis. 2021 Feb 23;16(1):98. doi: 10.1186/s13023-021-01735-2.
X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns.
Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features.
The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes.
We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.
X 连锁性汗孔发育不良（XLHED）是一种罕见的遗传性疾病，影响外胚层衍生物的正常发育，如毛发、皮肤、牙齿和汗腺。它是由 EDA 基因突变引起的，其特征是三联征，包括少毛症、少牙或无牙以及少汗或无汗，这可能导致危及生命的高热。尽管女性携带者的病情比男性患者轻，但她们也会出现症状，且具有高度的表型变异性。本研究旨在阐明具有相同 EDA 基因型的女性 XLHED 患者的表型差异是否可以通过不同的 X 染色体失活（XI）模式来解释。
本研究纳入了六个家族，每个家族由两位患有相同 EDA 变异的姐妹及其父母（母亲或父亲为变异携带者）组成。评估了与 XLHED 相关的症状，如出汗能力、牙齿状况、面部畸形和皮肤问题。我们通过人类雄激素受体检测法在周围血白细胞中确定了女性的个体 XI 模式，并将结果与表型特征进行了比较。
受影响女性的症状在家族内和家族间的显著差异无法用致病变异来解释。我们的研究对象与普通女性人群相比，在外周血白细胞中并未显示出更高的非随机 XI 率。此外，偏向于突变等位基因的 XI 模式与更严重的表型无关。
我们没有发现女性 XLHED 患者中 XI 偏向的证据，也没有发现 XLHED 相关表型特征与 XI 模式之间存在明显的相关性。表型变异性似乎是由其他遗传或表观遗传因素引起的。
