Center for Ectodermal Dysplasias and Department of Pediatrics, University Hospital Erlangen, Erlangen, Germany.
Clin Genet. 2019 Mar;95(3):427-432. doi: 10.1111/cge.13503.
Hypohidrotic ectodermal dysplasia (HED) is a rare genetic condition resulting from defective development of ectodermal derivatives, such as hair, teeth, and sweat glands. Autosomal recessive (AR) forms of HED may be caused by pathogenic variants of the ectodysplasin A1 receptor (EDAR) gene that encodes a receptor involved in the NF-κB signaling pathway. Here, we describe three cases of AR-HED in families of Turkish, Austrian, and German-American origin (with or without known consanguinity). In these cases, two out-of-frame deletions and a pathogenic missense variant of EDAR were found to be disease-causing due to reduced availability of the respective messenger RNA or impaired interaction of the encoded protein with its binding partner leading to diminished signal transduction. The same missense variant, c.1258C>T (p.Arg420Trp), has actually been reported to be restricted to the Icelandic population and to be associated with non-syndromic tooth agenesis but not HED. As our patient has no known relationship to Icelandic individuals and displays a rather severe HED phenotype, we suggest that EDAR-Arg420Trp is a more widespread variant, possibly with variable clinical expressivity.
少汗性外胚层发育不良（HED）是一种罕见的遗传性疾病，源于外胚层衍生物（如毛发、牙齿和汗腺）发育缺陷。常染色体隐性（AR）形式的 HED 可能由编码参与 NF-κB 信号通路的受体的外胚层发育不良素 A1 受体（EDAR）基因的致病性变异引起。在这里，我们描述了三个具有土耳其、奥地利和德裔美国人血统的 AR-HED 家族的病例（有或没有已知的近亲关系）。在这些病例中，由于相应的信使 RNA 的可用性降低或编码蛋白与其结合伴侣的相互作用受损导致信号转导减弱，发现两种无框缺失和一种 EDAR 的致病性错义变异是致病的。实际上，相同的错义变体 c.1258C>T（p.Arg420Trp）仅局限于冰岛人群，并与非综合征性牙齿缺失有关，但与 HED 无关。由于我们的患者与冰岛人没有已知的关系，并且表现出相当严重的 HED 表型，我们建议 EDAR-Arg420Trp 是一种更为广泛的变体，可能具有不同的临床表型。
