畸形发育不良患者样本的临床、遗传和骨科特点

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论证。畸发育不良（OMIM #222600）是一种罕见的常染色体隐性遗传性骨骼发育不良，与SLC26A2硫酸根转运体基因的同源或复合杂合子变异有关，从出生时就表现出来。其蛋白产物是硫酸根离子进入软骨细胞的跨膜转运蛋白，参与软骨基质蛋白聚糖的硫酸化过程，从而确保软骨骨化过程。对不同年龄段患者骨软骨发育不良的临床和影像学表现进行研究，将有助于改进诊断和矫形治疗策略。

目的。本研究的目的是了解俄罗斯因SLC26A2基因中先前描述的致病变体和新发现的变体而导致营养不良的患者的临床和遗传特征。

材料与方法。本研究对来自28个无血缘关系家庭的28名俄罗斯患者进行了全面检查，这些患者的年龄从3个月到34岁不等，均有发育不良的临床和影像学症状。采用系谱分析、临床检查、放射学检查和靶通过Sanger直接测序法对SLC26A2基因进行靶向诊断。

结果。通过对不同年龄段的俄罗斯发育不良患者样本进行综合分析，我们得以追踪从出生到成年的表型形成动态。分离出一组足以诊断新生儿营养不良性发育不良的典型临床和放射学特征，包括上下肢根状肌短缩、先天性马蹄内翻足、手部畸形、脱位和多关节挛缩。通过分子遗传学研究，我们在患者体内发现了14个SLC26A2基因变异体，其中9个是首次发现。在俄罗斯营养不良发育不良患者样本中发现的最常见变体是S.1957T>A(p.Cys653Ser)，占等位基因的50%。

结论。通过对俄罗斯营养不良患者样本进行临床和遗传分析，我们确定了临床和放射学特征的核心，并评估了该疾病临床表现的多态性。与之前研究的欧洲人群（包括芬兰）中诊断出的最多的营养不良症患者相比，俄罗斯人群中50%的营养不良发育病例是由c.1957T>A（P.CYS 653Ser）变体在同源变异或复合杂合状态下引起的。

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作者简介

Darya V. Gorodilova

Research Centre for Medical Genetics

Email: osipova@med-gen.ru
ORCID iD: 0000-0002-5863-3543
SPIN 代码: 9835-9616

MD, geneticist

俄罗斯联邦, 1 Moskvorechye str., Moscow, 115522

Tatiana V. Markova

Research Centre for Medical Genetics

Email: markova@med-gen.ru
ORCID iD: 0000-0002-2672-6294
SPIN 代码: 4707-9184

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

俄罗斯联邦, 1 Moskvorechye str., Moscow, 115522

Vladimir M. Kenis

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

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

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

俄罗斯联邦, Saint Petersburg

Aleksandra D. Akinshina

Priorov Central Institute for Trauma and Orthopedics

Email: akinishna@narod.ru
ORCID iD: 0000-0002-7319-5350
SPIN 代码: 8740-6190

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, 1 Moskvorechye str., Moscow, 115522

Olga A. Shchagina

Research Centre for Medical Genetics

Email: schagina@dnalab.ru
ORCID iD: 0000-0003-4905-1303
SPIN 代码: 9491-2411

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

俄罗斯联邦, 1 Moskvorechye str., Moscow, 115522

Elena L. Dadali

Research Centre for Medical Genetics

Email: genclinic@yandex.ru
ORCID iD: 0000-0001-5602-2805
SPIN 代码: 3747-7880

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

俄罗斯联邦, 1 Moskvorechye str., Moscow, 115522

Sergey I. Kutsev

Research Centre for Medical Genetics

编辑信件的主要联系方式.
Email: kutsev@mail.ru
ORCID iD: 0000-0002-3133-8018
SPIN 代码: 5544-8742

MD, PhD, Dr. Sci. (Med.), Professor, Сorresponding member of the Russian Academy of Sciences

俄罗斯联邦, 1 Moskvorechye str., Moscow, 115522

参考

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2. Fig. 1. X-ray image of the cervical spine in the lateral projection of a patient aged 6 years: cervical kyphosis with the apex at the level of the IV cervical vertebra (white-dotted line)

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3. Fig. 2. Spectrum of scoliotic spinal deformity in patients with diastrophic dysplasia: a, grade II scoliosis in a child aged 13 years; b, grade III scoliosis in a child aged 11 years; c, grade IV scoliosis in a child aged 14 years

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4. Fig. 3. Hands of patients with diastrophic dysplasia of different ages: a, patient aged 7.5 years: brachydactyly of all fingers, “hitchhiker’s thumb,” absence of interphalangeal skin folds, limited flexion in the metacarpophalangeal joints and, to a greater extent, interphalangeal joints II–V of the hands; b, patient aged 26 years: brachydactyly (mainly fingers II), clinodactyly of fingers II, III, and V on the left and finger III on the right, “hitchhiker’s thumb,” absence of interphalangeal skin folds, and significant limitation of flexion in the metacarpophalangeal joints and to a greater extent in the interphalangeal joints II–V of the hands

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5. Fig. 4. Ear cartilage deformity in patients with diastrophic dysplasia at different ages: a, the auricle in the acute period of cystic edema in a patient aged 3 months; b, residual deformity of the auricle due to cystic edema in a 7-year-old patient

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6. Fig. 5. Appearance and X-ray data of the feet of a patient with diastrophic dysplasia: a, varus deformities of the feet due to forefoot adduction (metatarsus adductus); b, radiograph of the foot in a standing lateral projection, the angle of talocalcaneal divergence is within normal limits (60°) indicating the absence of equinus and varus deformity of the hindfoot (black dashed lines), and dorsal displacement of the medial sphenoid bone (white arrow) is an indicator of forefoot supination; c, radiograph of the foot in a frontal view, satisfactory talocalcaneal divergence in the horizontal plane (45°), lateral decentration of the navicular bone (white arrow), medial subluxation of the first cuneo-metatarsal joint (black arrow), and duplication of the ossification nucleus of the medial sphenoid bone (circled white line)

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7. Fig. 6. Radiological changes in knee joint deformities in patients with diastrophic dysplasia: a, flexion contracture of 10°, epiphyseal deformity, and absence of the ossification nucleus of the patella; b, flexion contracture of 60°, epiphyseal deformity, multiple nuclei of ossification of the patella (white arrow); c, flexion contracture of 85°, epiphyseal deformity, partial arrest of the distal growth zone of the femur in the posterior part (black arrow), and “multilayered” patella (white arrow)

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8. Fig. 7. Changes in the hip joints in patients with diastrophic dysplasia: a, varus deformity (right, 105°; left, 95°) of the proximal femurs, femoral neck shortening, right hip dislocation, and subluxation on the left; b, varus deformity (right and left 100°) of the proximal femurs, femoral neck shortening, and subluxation of the hip on the left; c, varus deformity (right 85°, left 90°) of the proximal femurs, pronounced femoral neck shortening, and lesser trochanter hypertrophy

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