Abstract：
X-linked reticular pigmentary disorder (XLPDR) is a rare condition characterized by skin hyperpigmentation, ectodermal features, multiorgan inflammation, and recurrent infections. All probands identified to date share the same intronic hemizygous POLA1 hypomorphic variant (NM_001330360.2(POLA1):c.1393-354A > G) on the X chromosome. Previous studies have supported excessive type 1 interferon (IFN) inflammation and natural killer (NK) cell dysfunction in disease pathogenesis. Common null polymorphisms in filaggrin (FLG) gene underlie ichthyosis vulgaris and atopic predisposition.
A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment.
Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR.
WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation.
This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype-phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.
A 9-year-old boy born to non-consanguineous parents developed eczema with reticular skin hyperpigmentation in early infancy. He suffered recurrent chest infections with chronic cough, clubbing, and asthma, moderate allergic rhinoconjunctivitis with keratitis, multiple food allergies, and vomiting with growth failure. Imaging demonstrated bronchiectasis, while gastroscopy identified chronic eosinophilic gastroduodenitis. Interestingly, growth failure and bronchiectasis improved over time without specific treatment.
Whole-genome sequencing (WGS) using Illumina short-read sequencing was followed by both manual and orthogonal automated bioinformatic analyses for single-nucleotide variants, small insertions/deletions (indels), and larger copy number variations. NK cell cytotoxic function was assessed using 51Cr release and degranulation assays. The presence of an interferon signature was investigated using a panel of six interferon-stimulated genes (ISGs) by QPCR.
WGS identified a de novo hemizygous intronic variant in POLA1 (NM_001330360.2(POLA1):c.1393-354A > G) giving a diagnosis of XLPDR, as well as a heterozygous nonsense FLG variant (NM_002016.2(FLG):c.441del, NP_0020.1:p.(Arg151Glyfs*43)). Compared to healthy controls, the IFN signature was elevated although the degree moderated over time with the improvement in his chest disease. NK cell functional studies showed normal cytotoxicity and degranulation.
This patient had multiple atopic manifestations affecting eye, skin, chest, and gut, complicating the presentation of XLPDR. This highlights that common FLG polymorphisms should always be considered when assessing genotype-phenotype correlations of other genetic variation in patients with atopic symptoms. Additionally, while the patient exhibited an enhanced IFN signature, he does not have an NK cell defect, suggesting this may not be a constant feature of XLPDR.
摘要：
背景：X连锁网状色素沉着症（XLPDR）是一种罕见的以皮肤色素沉着为特征的疾病，外胚层特征,多器官炎症,和反复感染。迄今为止确定的所有先证者在X染色体上共享相同的内含子半合子POLA1双态变体（NM_001330360.2（POLA1）：c.1393-354A>G）。先前的研究支持过度的1型干扰素（IFN）炎症和自然杀伤（NK）细胞功能障碍在疾病发病机理中。丝聚蛋白（FLG）基因中常见的无效多态性是寻常型鱼鳞病和特应性易感性的基础。
方法：一个9岁男孩出生，父母非近亲在婴儿期早期出现了带有网状皮肤色素沉着的湿疹。他反复胸部感染并伴有慢性咳嗽，俱乐部,哮喘,中度过敏性鼻结膜炎伴角膜炎，多种食物过敏,和生长障碍呕吐。影像学显示支气管扩张，而胃镜检查发现慢性嗜酸性粒细胞性胃十二指肠炎。有趣的是,生长障碍和支气管扩张随着时间的推移而改善，无需特殊治疗。
方法：使用Illumina短读测序进行全基因组测序（WGS），然后进行单核苷酸变异体的手动和正交自动生物信息学分析，小插入/删除(indel)，和更大的拷贝数变化。使用51Cr释放和脱颗粒测定法评估NK细胞的细胞毒性功能。使用一组六个干扰素刺激的基因（ISG）通过QPCR研究了干扰素特征的存在。
结果：WGS在POLA1（NM_001330360.2（POLA1）：c.1393-354A>G）中鉴定出一个从头半合子内含子变体，从而诊断为XLPDR，以及杂合的无义FLG变体（NM_002016.2（FLG）：c.441del，NP_0020.1:p.（Arg151Glyfs*43））。与健康对照相比，尽管随着他的胸部疾病的改善程度随着时间的推移而缓和，但IFN标签升高。NK细胞功能研究显示正常的细胞毒性和脱粒。
结论：该患者有多种影响眼睛的特应性表现，皮肤,胸部，和直觉，使XLPDR的呈现复杂化。这突出表明，在评估特应性症状患者的其他遗传变异的基因型-表型相关性时，应始终考虑常见的FLG多态性。此外,虽然患者表现出增强的IFN签名，他没有NK细胞缺陷,这表明这可能不是XLPDR的恒定特征。
方法：一个9岁男孩出生，父母非近亲在婴儿期早期出现了带有网状皮肤色素沉着的湿疹。他反复胸部感染并伴有慢性咳嗽，俱乐部,哮喘,中度过敏性鼻结膜炎伴角膜炎，多种食物过敏,和生长障碍呕吐。影像学显示支气管扩张，而胃镜检查发现慢性嗜酸性粒细胞性胃十二指肠炎。有趣的是,生长障碍和支气管扩张随着时间的推移而改善，无需特殊治疗。
方法：使用Illumina短读测序进行全基因组测序（WGS），然后进行单核苷酸变异体的手动和正交自动生物信息学分析，小插入/删除(indel)，和更大的拷贝数变化。使用51Cr释放和脱颗粒测定法评估NK细胞的细胞毒性功能。使用一组六个干扰素刺激的基因（ISG）通过QPCR研究了干扰素特征的存在。
结果：WGS在POLA1（NM_001330360.2（POLA1）：c.1393-354A>G）中鉴定出一个从头半合子内含子变体，从而诊断为XLPDR，以及杂合的无义FLG变体（NM_002016.2（FLG）：c.441del，NP_0020.1:p.（Arg151Glyfs*43））。与健康对照相比，尽管随着他的胸部疾病的改善程度随着时间的推移而缓和，但IFN标签升高。NK细胞功能研究显示正常的细胞毒性和脱粒。
结论：该患者有多种影响眼睛的特应性表现，皮肤,胸部，和直觉，使XLPDR的呈现复杂化。这突出表明，在评估特应性症状患者的其他遗传变异的基因型-表型相关性时，应始终考虑常见的FLG多态性。此外,虽然患者表现出增强的IFN签名，他没有NK细胞缺陷,这表明这可能不是XLPDR的恒定特征。
