Clinical and genetic characteristics of rare variants of acromelic skeletal dysplasias caused by mutations in the FBN1 gene

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Abstract

BACKGROUND: Geleophysic dysplasia and acromicric dysplasia are rare hereditary diseases characterized by dwarfism and dysplastic skeletal features. In the literature, only a few cases of geleophysic dysplasia and acromicric dysplasia caused by mutations in the FBN1 gene are described.

CLINICAL CASES: A description of the clinical and genetic characteristics of three female patients with acromelic dysplasias caused by three types of missense mutations in the FBN1 gene is presented. In two patients, on the basis of clinical manifestations and radiographic examination, acromicric dysplasia, and in one patient — geleophysic dysplasia were diagnosed. It was shown that all identified mutations were localized in exons of the FBN1 gene encoding the amino acid sequence of the fifth domain, which has homology with transforming growth factor-beta.

DISCUSSION: We have analyzed the clinical and genetic correlations to confirm the previously stated hypothesis about the occurrence of a severe phenotype of geleophysic dysplasia in patients with the c.5206T> C mutation. This mutation is characterized by the replacement of cysteine by arginine in the position of the polypeptide chain leading to moderate clinical manifestations of acromicric dysplasia in patients with the c.5284 G> A (p. Gly1762Ser). It was shown that the previously undescribed substitution c.5177G> A (p.Gly1726Asp and another previously described mutation in this codon resulted in the replacement of glutamine with valine. This mutation causes the appearance of a less pronounced phenotype of AD.

CONCLUSIONS: Based on the results of the examination of three Russian patients and analysis of clinical and radiographic parameters described in the literature, we reported that mutations in the FBN1 gene disrupted the amino acid sequence of the fifth like transforming growth factor-beta domain of fibrillin type 1. Importantly, these mutations are responsible for the occurrence of geleophysic dysplasia and acromicric dysplasia. However, the most severe clinical manifestations were observed in patients with mutations leading to the substitution of cysteine for arginine at the position of the polypeptide chain 1736. This may lead to affecting the transforming growth factor-beta signaling pathway.

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About the authors

Tatyana V. Markova

Research Centre for Medical Genetics

Author for correspondence.
Email: markova@med-gen.ru
ORCID iD: 0000-0002-2672-6294
SPIN-code: 4707-9184

MD, PhD

Russian Federation, Moskvorechye str., Moscow, 115522

Vladimir M. Kenis

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

Email: kenis@mail.ru
ORCID iD: 0000-0002-7651-8485
SPIN-code: 5597-8832
http://www.rosturner.ru/kl4.htm

MD, PhD, D.Sc.

Russian Federation, Saint Petersburg

Evgenii V. Melchenko

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

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

MD, PhD

Russian Federation, Saint Petersburg

Tatyana S. Nagornova

Research Centre for Medical Genetics

Email: t.korotkaya90@gmail.com
ORCID iD: 0000-0003-4527-4518

MD, clinical geneticist

Russian Federation, 1 Moskvorechye str., Moscow, 115522

Aysylu F. Murtazina

Research Centre for Medical Genetics

Email: aysylumurtazina@gmail.com
ORCID iD: 0000-0001-7023-7378
SPIN-code: 9807-3783

MD, neurologist, doctor of functional diagnostics

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, D.Sc., Professor

Russian Federation, Moskvorechye str., Moscow, 115522

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2. Fig. 1. Proband 1, girl, 10 months old: a, appearance of the patient (disproportionate nanism, limb shortening, brachydactyly, flexion contractures of the fingers of the hand, and facial dysmorphism); b, radiograph of the hip joints in frontal projection (an increase in the cervicodiaphyseal angles, acetabular index, and hypoplasia of the nuclei of ossification of the femoral heads); c, X-ray of the spine in lateral projection (ovoid shape of the thoracic vertebral bodies without deviations of the axis)

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3. Fig. 2. Proband 2, girl, 3 years old: a, appearance of the patient (disproportionate dwarfism, short limbs, brachydactyly, flexion contractures of the interphalangeal joints of the hands, and features of the facial phenotype); b, radiograph of the hip joints in the frontal projection [increase in the cervicodiaphyseal angle (marked with white lines), acetabular index (marked with black lines), “coracoid” shape of the medial parts of the proximal femoral epiphysis (marked with white arrows)]; c, radiograph of the hand [short main phalanges of the fingers (outlined with a black line), short and wide middle, hypoplastic distal phalanges of the fingers (outlined with a white line), and medial “notch” of the base V (marked with a black arrow) and lateral II metacarpal bone (marked with white arrow)]

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4. Fig. 3. Proband 3, girl, 7 years old: a, appearance of the patient (short stature, pseudomuscular physique, short limbs, brachydactyly, contractures of the joints of the hands, and features of the facial phenotype); b, radiograph of the hip joints in the frontal projection [an increase in the cervico-shaft angle, acetabular index, decreased bone coverage of the femoral heads (marked with black arrows), a change in the shape of the proximal epiphysis of the femur with a “coracoid” shape of the medial sections (marked with white arrows)]; c, X-ray of the spine in lateral projection (ovoid shape of the vertebral bodies and a slight increase in lumbar lordosis); d, radiograph of the hand in frontal projection [short and wide phalanges of the fingers (marked with white arrows) and medial “notch” of the base of the V metacarpal bone (marked with a black arrow)]

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5. Fig. 4. Protein domain structure (top) and amino acid sequence of a transforming growth factor-â-like domain with indicated amino acid substitutions in patients (bottom)

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Copyright (c) 2021 Markova T.V., Kenis V.M., Melchenko E.V., Nagornova T.S., Murtazina A.F., Dadali E.L.

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