背景:多汗性外胚层发育不良(HED)是一种导致外胚层结构异常发育的遗传性疾病。这种罕见的情况主要影响头发,指甲,内分泌腺体,和牙齿。虽然HED可以由多种基因引起,EDA,EDAR,EDARADD,WNT10A基因约占病例的90%。值得注意的是,与EDA中的变体相关的HED形式,EDAR,或EDARADD基因可能由于常见信号通路的缺陷而表现出相似的表型。这些基因产物之间的适当相互作用对于核因子(NF-κB)信号通路的激活至关重要,随后调节目标基因的转录。EDARADD基因,特别是,藏有与HED相关的最罕见的变种之一。
方法:在Sanliurfa培训和研究医院的门诊医学遗传学诊所,对父母近亲出生的5岁和2岁的兄弟进行了检查,土耳其。两者都表现出相同的HED经典表型特征。老人的头发很稀疏,又黑又脆,稀疏的眉毛和睫毛,锥形上、下前磨牙,有牙体发育不全,宽间隔的牙齿,皮肤非常干燥,轻度突出的前额,和眶周皱纹。年轻的那个显示了同样的,但不那么严重,临床特征。经过全面检查和病史评估,靶向下一代测序分析在EDARADD中产生了新的纯合插入变体c.322_323insCGGGCp。(Arg108ProfsTer7)。该突变迄今为止在文献中没有报道。
结论:在本报告中,我们展示了两个兄弟姐妹表现出经典的HED症状和一个新的EDARADD基因插入变体,这导致移码引入终止密码子。两兄弟都从父母那里继承了这种突变,他们是相同变体的杂合携带者。本研究可能揭示了HED的致病机制,并扩大与这种情况相关的EDARADD基因变异的范围。
BACKGROUND: Hypohidrotic ectodermal dysplasia (HED) is a genetic disorder that results in the abnormal development of structures derived from ectodermal tissue. This rare condition predominantly affects the hair, nails, eccrine glands, and teeth. While HED can be caused by various genes, the EDA, EDAR, EDARADD, and WNT10A genes account for approximately 90% of cases. Notably, HED forms associated with variants in the EDA, EDAR, or EDARADD genes may exhibit similar phenotypes due to defects in a common signaling pathway. Proper interaction among the products of these genes is crucial for the activation of the nuclear factor (NF-κB) signaling pathway, which subsequently regulates the transcription of targeted genes. The EDARADD gene, in particular, harbors one of the rarest reported variants associated with HED.
METHODS: Five-and two-years-old brothers born into consanguineous parents were examined at our outpatient medical genetics clinic at Sanliurfa Training and Research Hospital, Turkey. Both displayed the same classical phenotypic features of HED. The elder had a very sparse dark and brittle hair, sparse eyebrows and eyelashes, conical upper and lower premolar teeth with hypodontia, widely spaced teeth, very dry skin, mildly prominent forehead, and periorbital wrinkles. The younger one showed the same, but less severe, clinical features. After thorough examination and patient history evaluation, targeted next-generation sequencing analysis yielded the novel homozygous insertion variant c.322_323insCGGGC p.(Arg108ProfsTer7) in EDARADD. The mutation has not been reported to date in the literature.
CONCLUSIONS: In this report, we present two siblings exhibiting classical HED symptoms and a novel insertion variant of the EDARADD gene, which leads to a frameshift introducing a stop codon. Both brothers inherited such mutation from their parents, who were heterozygous carriers of the same variant. The present study may shed light about the pathogenic mechanisms underlying HED, and expand the spectrum of EDARADD gene variants associated with this condition.