Clinical and genetic characteristics of primary hypertrophic osteoarthropathy

IF 4.3 3区 材料科学 Q1 ENGINEERING, ELECTRICAL & ELECTRONIC
E. Dadali, T. Markova, V. Kenis, T. Nagornova, S. Nikitin
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引用次数: 0

Abstract

Background. Primary hypertrophic osteoarthropathy is a rare genetically heterogeneous disease with three clinical variants. The classic one is a combination of hyperostosis, arthropathy and pachyderma and two variants with damage to only bone structures or pachyderma. Two genes responsible for the occurrence of primary hypertrophic osteoarthropathy have been identified: HPGD (debut age up to one year) and SLCO2A1 (debut in puberty and adolescence), whose products are involved in prostaglandin E2 metabolism. Two recurrent variants were identified in the HPGD gene: c.175_176delCT(p.Leu59fs) in patients from Europe and c.310_311delCT in patients from China. There were no clinical and genetic correlations in patients with different variants in the identified genes, which may be due to a small number of observations. The analysis of clinical manifestations in patients with newly identified variants or previously unidentified combinations of variants in a compound‑heterozygous state helps to understand the pathogenesis and prognosis of the course of the disease.Aim. To present the clinical and genetic characteristics of two Russian patients with primary hypertrophic osteoarthropathy caused by a newly identified combination of nucleotide variants in a compound‑heterozygous state in the HPGD and SLCO2A1 genes.Materials and methods. Clinical examination, radiography of the skeleton and chest, electrocardiography, echocardiography. Confirmation of the pathogenicity of the identified variants and clarification of the type of disease was carried out using automatic Sanger sequencing.Results. The clinical and genetic characteristics of two unrelated patients with primary hypertrophic osteoarthropathy caused by an undescribed combination of variants in the compound heterozygous state in the HPGD and SLCO2A1 genes were analyzed. In a patient with variants in the SLCO2A1 gene, the disease debuts at the age of 14 with deformities of the fingers, nails on the hands and feet, followed by the addition of burning pain in the distal parts of the arms and legs. At the age of 33, the examination revealed deformity of the fingers of the hands and feet by the type of drumsticks and nails by the type of watch glasses, enlargement of the knee joints, pronounced arthralgia. There were no signs of pachyderma. The new generation sequencing revealed two variants in the SLCO2A1 gene c.764G>A(p.Gly255Glu) in exon 6 and c.1333C>T(p.Arg445Cys) in exon 10. These variants were identified earlier in a compound‑heterozygous combination with other variants in patients with the classical phenotype of the disease, which were not present in the patient we observed. A feature of the case was pronounced hyperhidrosis and burning pain in the extremities, which may be due to stimulation of nociceptors in the musculoskeletal structures.Deformities of the fingers, nails of the hands and feet occurred in a patient with variants in the HPGD gene at 6 months. At the age of 9 years, a change in shape, stiffness and arthralgia of the knee and elbow joints without pachyderma were revealed. The identified variant with c.175_176delCT(p.Leu59fs) in this gene is often found in patients from European countries, and the other is c.1A>G(p.Met1?) discovered for the first time.Conclusion. The results allow us to conclude that when we found combinations of two variants in the HPGD and SLCO2A1 genes, there will be no pachyderma in the spectrum of clinical manifestations of primary hypertrophic osteoarthropathy. Sequencing of the new generation exome is the optimal diagnostic method.
原发性肥厚性骨关节病的临床和遗传特征
背景。原发性肥厚性骨关节病是一种罕见的遗传异质性疾病,有三种临床变异。经典的一种是骨质增生、关节病和厚皮病的组合,还有两种变体,只损害骨结构或厚皮病。已经确定了两个与原发性肥厚性骨关节病发生有关的基因:HPGD(首次出现年龄高达1岁)和SLCO2A1(首次出现在青春期和青春期),其产物参与前列腺素E2代谢。在HPGD基因中发现了两种复发变异体:欧洲患者的c.175_176delCT(p.Leu59fs)和中国患者的c.310_311delCT。在已鉴定的基因中,不同变异的患者没有临床和遗传相关性,这可能是由于少量的观察结果。分析新发现的变异体或以前未发现的复合杂合变异体组合患者的临床表现,有助于了解疾病的发病机制和病程预后。介绍两名俄罗斯原发性肥厚性骨关节病患者的临床和遗传特征,这些患者是由新近发现的HPGD和SLCO2A1基因中处于复合杂合状态的核苷酸变异组合引起的。材料和方法。临床检查,骨骼和胸部x线摄影,心电图,超声心动图。采用自动桑格测序法确认已鉴定的变异的致病性并澄清疾病类型。分析了两例由HPGD和SLCO2A1基因复合杂合状态的未描述变异组合引起的无相关性的原发性肥厚性骨关节病患者的临床和遗传特征。在患有SLCO2A1基因变异的患者中,这种疾病在14岁时首次出现,手指,手和脚的指甲畸形,随后在手臂和腿部的远端部位增加灼痛。在33岁的时候,检查显示手脚的手指和脚的畸形类型的鼓槌和指甲类型的手表眼镜,膝关节扩大,明显的关节痛。没有厚皮病的迹象。新一代测序结果显示,SLCO2A1基因外显子c.764G>A(p.Gly255Glu)位于第6外显子,c.1333C>T(p.Arg445Cys)位于第10外显子。这些变异早期在具有该疾病经典表型的患者中与其他变异的复合杂合组合中被发现,这些变异在我们观察的患者中不存在。该病例的一个特征是四肢明显多汗和灼痛,这可能是由于肌肉骨骼结构中伤害感受器的刺激。患有HPGD基因变异的患者在6个月时出现手指、手指甲和脚的畸形。在9岁时,发现无厚皮病的膝关节和肘关节形状、僵硬和关节痛的变化。该基因的c.175_176delCT(p.Leu59fs)变异常见于欧洲国家的患者,另一个为首次发现的c.1A>G(p.Met1?)。结果使我们得出结论,当我们发现HPGD和SLCO2A1基因的两种变异组合时,原发性肥厚性骨关节病的临床表现谱中不会出现厚皮病。新一代外显子组测序是最佳诊断方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
7.20
自引率
4.30%
发文量
567
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