软骨发育不全和假性软骨发育不全的鉴别诊断原则

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论证。软骨发育不全和假性软骨发育不全是遗传性系统性骨骼发育不良，其临床表现有某些相似之处，但病因机制不同。分子遗传学诊断采用多种方法。这些疾病具有共同的表型特征，在对患者进行临床检查、DNA诊断计划以及及时发现神经外科和骨科并发症时，往往会使鉴别诊断复杂化。

目的。该研究旨在确定软骨发育不全和假性软骨发育不全的鉴别诊断标准，并优化其分子遗传诊断策略。

材料与方法。对来自74个无亲属关系家庭的76名年龄在1个月至18岁之间有软骨发育不全和假性软骨发育不全表型体征的儿童进行了全面检查。通过家谱分析、病史资料、临床检查、按照标准方法进行的神经系统检查和放射学检查来明确诊断。通过寻找表皮生长因子受体3（FGFR3）基因的频繁突变、估算位于COMP基因第13外显子中的GAC重复序列的数量，以及对由166个导致遗传性骨骼病变的基因组成的新一代靶向面板进行测序，对疾病诊断进行了分子遗传学确认。

结果。通过对比分析软骨发育不全与假性软骨发育不全患者的表型特征，明确了它们的鉴别诊断标准。在软骨发育不全症中，主要特征是出生时就不成比例的侏儒症、巨颅症和面部畸形，这与假性软骨发育不全症的特征不符。特定的放射学特征对于假性软骨发育不全的鉴别诊断具有重要意义，在转诊患者进行分子遗传学分析时应加以考虑。经证实，绝大多数软骨发育不全患者的FGFR3基因中存在c.1138G>A的重大突变。在27%的假性软骨发育不良患者中，检测到COMP基因中的GAC重复缺失（c.1417_1419del）。基于这些结果，我们得出结论，最好优先分析FGFR3和COMP基因中的这两个突变。如果没有找到突变基因，则应继续进行诊断搜索，使用由166个导致遗传性骨骼病变的基因组成的目标基因面板或完整的外显子组测序。

结论。通过对软骨发育不全和假性软骨发育不全患者样本的临床、放射学和分子遗传学特征进行分析，并结合对文献数据的研究，我们得以明确这些疾病的鉴别诊断标准，并优化其分子遗传学诊断算法。

作者简介

Tatiana V. Markova

Research Centre for Medical Genetics

Email: markova@med-gen.ru
ORCID iD: 0000-0002-2672-6294
SPIN 代码: 4707-9184
Scopus 作者 ID: 57204436561
Researcher ID: AAJ-8352-2021

MD, PhD, Cand. Sci. (Med.)

俄罗斯联邦, Moscow

Vladimir M. Kenis

H. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery; North-Western State Medical University named after I.I. Mechnikov

Email: kenis@mail.ru
ORCID iD: 0000-0002-7651-8485
SPIN 代码: 5597-8832
Scopus 作者 ID: 36191914200
Researcher ID: K-8112-2013
http://www.rosturner.ru/kl4.htm

MD, PhD, Dr. Sci. (Med.), Professor

俄罗斯联邦, Saint Petersburg; Saint Petersburg

Evgenii V. Melchenko

H. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery

Email: emelchenko@gmail.com
ORCID iD: 0000-0003-1139-5573
SPIN 代码: 1552-8550
Scopus 作者 ID: 55022869800

MD, PhD, Cand. Sci. (Med.)

俄罗斯联邦, Saint Petersburg

Dmitry A. Reshchikov

Russian Children’s Clinical Hospital of the Russian National Research Medical University named after N.I. Pirogov

Email: reshchikovdm@gmail.com
ORCID iD: 0000-0001-8146-5501
SPIN 代码: 4821-5487

Neurosurgeon

俄罗斯联邦, Moscow

Aynur E. Alieva

Research Centre for Medical Genetics

Email: alieva.aynur1996@gmail.com
ORCID iD: 0000-0003-1048-075X

Resident Doctor

俄罗斯联邦, Moscow

Darya V. Osipova

Research Centre for Medical Genetics

Email: osipova.dasha2013@yandex.ru
ORCID iD: 0000-0002-5863-3543
SPIN 代码: 9835-9616
Scopus 作者 ID: 57218497500
Researcher ID: AAA-6909-2022

MD, Geneticist

俄罗斯联邦, Moscow

Liudmila A. Bessonova

Research Centre for Medical Genetics

Email: bessonovala@yandex.ru
ORCID iD: 0000-0002-5946-4577

MD, Geneticist

俄罗斯联邦, Moscow

Tatiana S. Nagornova

Research Centre for Medical Genetics

Email: t.korotkaya90@gmail.com
ORCID iD: 0000-0003-4527-4518
SPIN 代码: 6032-2080

MD, Laboratory Geneticist

俄罗斯联邦, Moscow

Natalya N. Vasserman

Research Centre for Medical Genetics

Email: vasserman@dnalab.ru
ORCID iD: 0000-0001-5007-6028
SPIN 代码: 2936-7200

MD, PhD, Cand. Sci. (Med.)

俄罗斯联邦, Moscow

Natalya Yu. Ogorodova

Research Centre for Medical Genetics

Email: ognatashka@mail.ru
ORCID iD: 0000-0001-6151-5022
SPIN 代码: 4300-7904

MD, Laboratory Geneticist

俄罗斯联邦, Moscow

Olga A. Shchagina

Research Centre for Medical Genetics

Email: schagina@dnalab.ru
ORCID iD: 0000-0003-4905-1303
Scopus 作者 ID: 25422833100
Researcher ID: W-4835-2018

MD, PhD, Cand. Sci. (Med.)

俄罗斯联邦, Moscow

Elena L. Dadali

Research Centre for Medical Genetics

编辑信件的主要联系方式.
Email: genclinic@yandex.ru
ORCID iD: 0000-0001-5602-2805
SPIN 代码: 3747-7880
Scopus 作者 ID: 6701733307
Researcher ID: AFG-0883-2022

MD, PhD, Dr. Sci. (Med.), Professor

俄罗斯联邦, Moscow

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2. 图1. 软骨发育不全（a、b）和假性软骨发育不全（c、d）患者的外观。这两名患者都有不成比例的发育迟缓、肢体短小、胸廓畸形、肘关节伸展不全、下肢畸形和肱骨半截畸形。仅在一名软骨发育不全患者中发现了大颅骨（脑颅骨增大、额顶骨尖突出）和面部畸形（中面部发育不良）

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3. 图2. 软骨发育不全（a）和假性软骨发育不全（b）患者手部外观。两名患者都被发现患有手足畸形。只有一名软骨发育不全的患者出现了等长指（手指长度相当）和三叉戟症状（手指的指骨分叉，二至三指的末节指骨和三至四指的末节指骨分叉更明显）

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4. 图3. 软骨发育不全（a）和假性软骨发育不全（b）患者胸椎和腰椎的侧位投影照片：a - 椎体远端生理性骨化，椎体轮廓呈方形（白色箭头）；胸椎后凸平滑（黄线）， 病理性胸腰椎后凸（红线），腰椎前凸增强（蓝线）； b - 椎体骨突异常骨化，椎体前部舌状突起（白色箭头）；生理性胸椎后凸（黄线），腰椎前凸适度增加（蓝线）

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5. 图4. 软骨发育不全患者（a）和假性软骨发育不全患者（b）髋关节和股骨的直接投照X光片：a - 髋臼穹隆水平位置（白线）、坐骨切迹狭窄（白色箭头）、三叉症状 （黑色箭头）、髂骨翼方形轮廓（白色轮廓）；b - 髋臼穹隆倾斜（白线）、髂骨翼椭圆形轮廓（白色轮廓）

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6. 图5. 一名软骨发育不全患者（a）和一名假性软骨发育不全患者（b）的手部X光片：两例患者的手部均有中度尺侧偏斜和肱骨发育不全（用白色轮廓标出）；假性软骨发育不全患者的掌骨缩短，杯状骨骺增大，骨骺呈小圆球状（白色箭头） 图6. COMP基因致病性变异的域特异性分布。COMP基因中新发现的变异用红色标出，以前描述过的变异用蓝色标出，频繁发生的变异用绿色标出

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7. 图6. COMP基因致病性变异的域特异性分布。COMP基因中新发现的变异用红色标出，以前描述过的变异用蓝色标出， 频繁发生的变异用绿色标出

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版权所有 © Markova T.V., Kenis V.M., Melchenko E.V., Reshchikov D.A., Alieva A.E., Osipova D.V., Bessonova L.A., Nagornova T.S., Vasserman N.N., Ogorodova N.Y., Shchagina O.A., Dadali E.L., 2023

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