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Orphanet Journal of Rare Diseases Oct 2023Fetal skeletal dysplasia is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims...
BACKGROUND
Fetal skeletal dysplasia is a diverse group of degenerative diseases of bone and cartilage disorders that can lead to movement disorder and even death. This study aims to evaluate the diagnostic yield of sonographic examination and genetic testing for fetal skeletal dysplasia.
METHODS
From September 2015 to April 2021, the study investigated 24 cases with suspected short-limb fetuses, which were obtained from Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology. To identify the causative gene, multiple approaches (including karyotype analysis, copy number variations and whole exome sequencing) were performed on these fetuses. And further segregation analysis of the candidate variant was performed in parents by using Sanger sequencing.
RESULTS
① Out of 24 cases, likely pathogenic variants in FGFR3, FBN2, COL1A2, CUL7 and DYNC2H1 were detected in 6 cases; pathogenic variants in FGFR3, IMPAD1 and GORAB were identified in other 6 cases; and variants in WNT1, FBN1, OBSL1, COL1A1, DYNC2H1 and NEK1, known as Variant of Undetermined Significance, were found in 4 cases. There were no variants detected in the rest 8 cases by the whole exome sequencing. ② Of 24 cases, 12 (50%) were found to carry variants (pathogenic or likely pathogenic) in seven genes with 12 variants. Four fetuses (16.7%) had variants of uncertain significance.
CONCLUSION
Genetic testing combining with ultrasound scanning enhances the accurate diagnosis of fatal skeletal dysplasia in utero, and then provides appropriate genetic counseling.
Topics: Humans; DNA Copy Number Variations; Genetic Testing; Fetus; Osteochondrodysplasias; Cytoskeletal Proteins
PubMed: 37875969
DOI: 10.1186/s13023-023-02955-4 -
American Journal of Physiology. Cell... Aug 2022The extracellular matrix is an intricate and essential network of proteins and nonproteinaceous components that provide a conducive microenvironment for cells to... (Review)
Review
The extracellular matrix is an intricate and essential network of proteins and nonproteinaceous components that provide a conducive microenvironment for cells to regulate cell function, differentiation, and survival. Fibronectin is one key component in the extracellular matrix that participates in determining cell fate and function crucial for normal vertebrate development. Fibronectin undergoes time-dependent expression patterns during stem cell differentiation, providing a unique stem cell niche. Mutations in fibronectin have been recently identified to cause a rare form of skeletal dysplasia with scoliosis and abnormal growth plates. Even though fibronectin has been extensively analyzed in developmental processes, the functional role and importance of this protein and its various isoforms in skeletal development remain less understood. This review attempts to provide a concise and critical overview of the role of fibronectin isoforms in cartilage and bone physiology and associated pathologies. This will facilitate a better understanding of the possible mechanisms through which fibronectin exerts its regulatory role on cellular differentiation during skeletal development. The review discusses the consequences of mutations in fibronectin leading to corner fracture type spondylometaphyseal dysplasia and presents a new outlook toward matrix-mediated molecular pathways in relation to therapeutic and clinical relevance.
Topics: Cell Differentiation; Extracellular Matrix; Fibronectins; Humans; Osteochondrodysplasias; Protein Isoforms
PubMed: 35759430
DOI: 10.1152/ajpcell.00226.2022 -
European Journal of Medical Genetics Aug 2022Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available,...
Sedaghatian type spondylometaphyseal dysplasia (SSMD) is a rare skeletal dysplasia with only 24 reported cases to date. Despite the limited literature available, evidence suggests this is a multi-system disorder, with neurological and cardiovascular abnormalities reported in addition to the skeletal features. We report a new family with two affected siblings and detailed phenotypic description of the affected proband. Diagnosis in the neonatal period led to retrospective genetic diagnosis of a previous affected pregnancy that was terminated due to severe ventriculomegaly. We suggest that a diagnosis of SSMD should be considered when shortened long bones are found in combination with significant brain abnormalities.
Topics: Humans; Infant, Newborn; Osteochondrodysplasias; Radiography; Retrospective Studies; Siblings
PubMed: 35718083
DOI: 10.1016/j.ejmg.2022.104541 -
American Journal of Medical Genetics.... Dec 2020Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive... (Review)
Review
Skeletal dysplasias (SD) are disturbances in growth due to defects intrinsic to the bone and/or cartilage, usually affecting multiple bones and having a progressive character. In this article, we review the state of clinical and research SD resources available in Latin America, including three specific countries (Brazil, Argentina, and Chile), that have established multidisciplinary clinics for the care of these patients. From the epidemiological point of view, the SD prevalence of 3.2 per 10,000 births from nine South American countries included in the ECLAMC network represents the most accurate estimate not just in Latin America, but worldwide. In Brazil, there are currently five groups focused on SD. The data from one of these groups including the website www.ocd.med.br, created to assist in the diagnosis of SD, are highlighted showing that telemedicine for this purpose represents a good strategy for the region. The experience of more than 30 years of the SD multidisciplinary clinic in an Argentinian Hospital is presented, evidencing a solid experience mainly in the follow-up of the most frequent SD, especially those belonging the FGFR3 group and OI. In Chile, a group with 20 years of experience presents its work with geneticists and pediatricians, focusing on diagnostic purposes and clinical management. Altogether, although SD health-care and research activities in Latin America are in their early stages, the experience in these three countries seems promising and stimulating for the region as a whole.
Topics: Argentina; Bone and Bones; Humans; Latin America; Osteochondrodysplasias; Prevalence
PubMed: 33219737
DOI: 10.1002/ajmg.c.31861 -
Frontiers in Endocrinology 2020Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the... (Review)
Review
Skeletal dysplasias are a diverse group of heritable diseases affecting bone and cartilage growth. Throughout the years, the molecular defect underlying many of the diseases has been identified. These identifications led to novel insights in the mechanisms regulating bone and cartilage growth and homeostasis. One of the pathways that is clearly important during skeletal development and bone homeostasis is the Wingless and int-1 (WNT) signaling pathway. So far, three different WNT signaling pathways have been described, which are all activated by binding of the WNT ligands to the Frizzled (FZD) receptors. In this review, we discuss the skeletal disorders that are included in the latest nosology of skeletal disorders and that are caused by genetic defects involving the WNT signaling pathway. The number of skeletal disorders caused by defects in WNT signaling genes and the clinical phenotype associated with these disorders illustrate the importance of the WNT signaling pathway during skeletal development as well as later on in life to maintain bone mass. The knowledge gained through the identification of the genes underlying these monogenic conditions is used for the identification of novel therapeutic targets. For example, the genes underlying disorders with altered bone mass are all involved in the canonical WNT signaling pathway. Consequently, targeting this pathway is one of the major strategies to increase bone mass in patients with osteoporosis. In addition to increasing the insights in the pathways regulating skeletal development and bone homeostasis, knowledge of rare skeletal dysplasias can also be used to predict possible adverse effects of these novel drug targets. Therefore, this review gives an overview of the skeletal and extra-skeletal phenotype of the different skeletal disorders linked to the WNT signaling pathway.
Topics: Animals; Bone Diseases; Bone and Bones; Genetic Diseases, Inborn; Humans; Musculoskeletal Abnormalities; Wnt Signaling Pathway
PubMed: 32328030
DOI: 10.3389/fendo.2020.00165 -
Frontiers in Pediatrics 2023Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or... (Review)
Review
Children with skeletal dysplasia are frequently referred to pediatric endocrinologists due to short stature. These children may present with disproportionate growth or medical histories that point to a skeletal dysplasia. This primer will discuss when to be concerned about skeletal dysplasia, the initial steps in evaluation for a skeletal dysplasia, and new therapies that are either recently approved or in development.
PubMed: 37675393
DOI: 10.3389/fped.2023.1229666 -
BMC Musculoskeletal Disorders Jul 2021Skeletal dysplasia is a heterogeneous group of disorders resulting from different genetic variants in humans. The current study was designed to identify the genetic...
BACKGROUND
Skeletal dysplasia is a heterogeneous group of disorders resulting from different genetic variants in humans. The current study was designed to identify the genetic causes of skeletal dysplasia and short stature in two consanguineous families from Pakistan, both comprised of multiple affected individuals. Patients in one family had proportionate short stature with reduced head circumference while affected individuals in the other family had disproportionate short stature.
METHODS
Clinical data were obtained and radiological examinations of the index patients were completed. Whole genome sequencing for probands from both families were performed followed by Sanger sequencing to confirm segregation of identified variants in the respective families. In-silico pathogenicity score prediction for identified variant and amino acid conservation analysis was completed.
RESULTS
Whole Genome Sequencing identified a known biallelic variant c.6176_6189delGTCAGCTGCCGAAG; p.(Gln2060ArgfsTer48) in PCNT gene and a novel biallelic variant c.174delC; p.(Asp60ThrfsTer7) in RAB33B gene respectively in affected members of the two families. Clinical imaging revealed platyspondyly and varus deformity in the legs of the affected members in the first family. Radiographs indicated severe platyspondyly, genu valgus deformity of legs and pectus carinatum for the patients in the second family.
CONCLUSION
In this study we report the phenotypes and genetic variants in two unrelated families with two distinct forms of skeletal dysplasia. This study strengthens the previous findings that patients harboring PCNT variants are phenotypically homogeneous and also extends the genotypic spectrum of RAB33B variants.
Topics: Consanguinity; Humans; Osteochondrodysplasias; Pakistan; Pedigree; Phenotype; rab GTP-Binding Proteins
PubMed: 34284742
DOI: 10.1186/s12891-021-04503-2 -
Genetics in Medicine : Official Journal... Jun 2010The skeletal dysplasias (osteochondrodysplasias) are a heterogeneous group of more than 350 disorders frequently associated with orthopedic complications and varying... (Review)
Review
The skeletal dysplasias (osteochondrodysplasias) are a heterogeneous group of more than 350 disorders frequently associated with orthopedic complications and varying degrees of dwarfism or short stature. These disorders are diagnosed based on radiographic, clinical, and molecular criteria. The molecular mechanisms have been elucidated in many of these disorders providing for improved clinical diagnosis and reproductive choices for affected individuals and their families. An increasing variety of medical and surgical treatment options can be offered to affected individuals to try to improve their quality of life and lifespan.
Topics: Humans; Osteochondrodysplasias; Quality of Life
PubMed: 20556869
DOI: 10.1097/GIM.0b013e3181daae9b