Clinical, genetic, and orthopedic characteristics of large group of patients with diastrophic dysplasia

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Abstract

BACKGROUND: Diastrophic dysplasia (OMIM #222600) is a rare congenital autosomal recessive skeletal dysplasia associated with homozygous or compound-heterozygous variants in the sulfate transporter gene SLC26A2. Clinical and radiological descriptions of diastrophic dysplasia in patients of different ages will help improve the diagnosis and orthopedic treatment.

AIM: To describe clinical and genetic characteristics of Russian patients with diastrophic dysplasia caused by previously described and newly identified pathogenic SLC26A2 variants.

MATERIALS AND METHODS: A comprehensive examination of 28 Russian patients from 28 unrelated families aged 3 months to 34 years with clinical and radiological signs of diastrophic dysplasia was performed. To confirm the diagnosis, genealogical analysis, clinical examination, radiography, and targeted research of SLC26A2 using direct Sanger sequencing were performed.

RESULTS: Typical clinical and radiological signs sufficient for diagnosing diastrophic dysplasia in newborns have been identified, which included rhizo/mesomelic shortening of the upper and lower extremities, congenital clubfoot, hand anomalies, multiple dislocations, and joint contractures. In our patients, 14 SLC26A2 variants were identified, 9 of which were first discovered. The most common variant identified in Russian patients with diastrophic dysplasia was c.1957T>A (p.Cys653Ser), which accounted for 50% of the alleles.

CONCLUSIONS: Clinical and genetic analyses of Russian patients with diastrophic dysplasia made it possible to identify the core clinical and radiological signs and evaluate the polymorphism of the clinical manifestations of the disease. In contrast to previously examined patients from European populations (including Finland with the largest number of patients with diastrophic dysplasia), 50% of the cases in the Russian population are caused by the c.1957T>A (p.Cys653Ser) homozygous or compound-heterozygous variant.

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About the authors

Darya V. Gorodilova

Research Centre for Medical Genetics

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

MD, geneticist

Russian Federation, 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-code: 4707-9184

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

Russian Federation, 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-code: 5597-8832
http://www.rosturner.ru/kl4.htm

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

Russian Federation, 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-code: 1552-8550

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

Russian Federation, Saint Petersburg

Aleksandra D. Akinshina

Priorov Central Institute for Trauma and Orthopedics

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

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

Russian Federation, Moscow

Natalya Yu. Ogorodova

Research Centre for Medical Genetics

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

MD, laboratory geneticist

Russian Federation, 1 Moskvorechye str., Moscow, 115522

Olga A. Shchagina

Research Centre for Medical Genetics

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

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

Russian Federation, 1 Moskvorechye str., Moscow, 115522

Elena L. Dadali

Research Centre for Medical Genetics

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

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

Russian Federation, 1 Moskvorechye str., Moscow, 115522

Sergey I. Kutsev

Research Centre for Medical Genetics

Author for correspondence.
Email: kutsev@mail.ru
ORCID iD: 0000-0002-3133-8018
SPIN-code: 5544-8742

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

Russian Federation, 1 Moskvorechye str., Moscow, 115522

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Supplementary files

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

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3. Fig. 2. The spectrum of scoliotic spinal deformity in patients with diastrophic dysplasia: a - second degree scoliosis in a child aged 13 years; b — grade III scoliosis in a child aged 11 years; c — IV degree scoliosis in a child aged 14 years

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

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5. Fig. 4. Deformation of the external ear in patients with diastrophic dysplasia at different ages: a — appearance of the auricle in the acute period of cystic edema in a patient aged 3 months; b — residual deformation 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 adduction of the anterior sections (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), dorsal displacement of the medial wedge-shaped bone (white arrow) is an indicator of supination of the forefoot foot department; c — radiograph of the foot in a direct projection: satisfactory talocalcaneal divergence in the horizontal plane (45°), lateral decentration scaphoid (white arrow), medial subluxation of the first sphenometatarsal joint (black arrow), duplication of the ossification nucleus of the medial sphenoid (outlined by a white line)

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7. Fig. 6. The range of radiological changes in deformities of the knee joints in patients with diastrophic dysplasia: a - flexion contracture - 10°, deformation of the epiphyses, absence of the ossification nucleus of the patella; b — flexion contracture — 60°, deformation of the epiphyses, multiple ossification nuclei of the patella (white arrow); c — flexion contracture — 85°, deformation of the epiphyses, partial arrest of the distal growth zone of the femur in the posterior part (black arrow), “multilayered” patella (white arrow)

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

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