Abstract
Relevance. Acromezomelic dysplasia Maroteaux type (AMDM) is a rare variant of autosomal recessive skeletal disorder. The disease is caused by mutations in the NPR2 gene, coding the protein product which is one of the main regulators of endochondral ossification. To date, 49 mutations in this gene have been identified, more than half of which are missense substitutions. The presence of polymorphism of phenotypic manifestations makes it necessary to describe the features of clinical and radiological characteristics of the disease in patients with newly identified mutations in the gene, which will help to optimize its diagnosis. Case presentation. The clinical and radiological characteristics of two siblings with newly identified mutations c.125_126insTGGCG (p.Trp42CysfsTer12) and (p.Arg767Ter) in the NPR2 gene are described. Intra-family polymorphism of clinical manifestations is shown. Discussion. Clinical manifestations and radiological data in two siblings with AMDM caused by new mutations in the NPR2 gene and analysis of the literature data allowed us to conclude that there is no correlation of the severity of clinical signs and the type of mutations in the gene. Patients are born with normal growth and weight, and clinical manifestations (disproportionate dwarfism) appeared during the first year of life. The main radiological signs are shortening of tubular bones, most pronounced in the upper limbs and wedge-shaped formation of the vertebral bodies. Genotype-phenotype correlations confirmed the hypothesis that the majority of mutations leading to the disease is localized within the ligand-binding and guanylate cyclase domains. Conclusion. The obvious genetic heterogeneity, the similarity of the clinical manifestations of individual nosological groups of skeletal dysplasias, as well as the presence of intrafamily and interfamily polymorphism of clinical manifestations allows us to consider sequencing of a clinical exome or whole exome as the optimal method for diagnosing this group of diseases.
About the authors
Research Centre for Medical Genetics
Email: markova@med-gen.ru
ORCID iD: 0000-0002-2672-6294
Tatyana V. Markova — Cand. Sci. (Med.), Geneticist
Moscow
Россия
H. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery
Author for correspondence.
Email: kenis@mail.ru
Vladimir M. Kenis — Dr. Sci. (Med.), Deputy Director
St. Petersburg
Россия
Research Centre for Medical Genetics
Email: mironovich.olga@med-gen.ru
ORCID iD: 0000-0003-0351-1271
Olga L. Mironovich — Cand. Sci. (Med.), Researcher
Moscow
Россия
Research Centre for Medical Genetics
Email: schagina@dnalab.ru
ORCID iD: 0000-0003-4905-1303
Olga A. Shchagina — Cand. Sci. (Med.), Head of the laboratory of Molecular Genetics
Moscow
Россия
Research Centre for Medical Genetics
Email: t.korotkaya90@gmail.com
ORCID iD: 0000-0003-4527-4518
Tatyana S. Nagornova — Geneticist
Moscow
Россия
H. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma Surgery
Email: emelchenko@gmail.com
ORCID iD: 0000-0003-1139-5573
Evgeniy V. Melchenko — Cand. Sci. (Med.), Researcher
St. Petersburg
Россия
Research Centre for Medical Genetics
Email: genclinic@yandex.ru
ORCID iD: 0000-0001-5602-2805
Elena L. Dadali — Dr. Sci. (Med.), Professor, Head of the clinical department
Moscow
Россия