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Spondyloepiphyseal Dysplasia Congenita

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Spondyloepiphyseal Dysplasia Congenita. Core disease mechanisms, molecular...

2026-04-02
Asta MONDO:0008471 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Spondyloepiphyseal Dysplasia Congenita. Core disease mechanisms, molecular...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Exploring and expanding the phenotype and genotype diversity in seven Chinese families with spondylo-epi-metaphyseal dysplasia

  • Authors: Shanshan Lv, Jiao Zhao, Li Liu, C. Wang, H. Yue et al.
  • Year: 2022
  • Venue: Frontiers in Genetics
  • URL: https://www.semanticscholar.org/paper/9a62aa326fc1ed5c4ff713faa72491102dd12c0f
  • DOI: 10.3389/fgene.2022.960504
  • PMID: 36118854
  • PMCID: 9473317
  • Citations: 2
  • Summary: The phenotype and genetic spectrum of SEMD is expanded and evidence for the phenotype–genotype relations is provided, aiding future molecular and clinical diagnosis as well as procreative management of SEMd.
  • Evidence snippets:
  • Snippet 1 (score: 0.579) > For example, SED with different clinical manifestations can be divided into spondyloepiphyseal dysplasia congenita (SEDC, OMIM# 183900), spondyloepiphyseal dysplasia-Kimberley type (SED-KT, OMIM# 608361), and spondyloepiphyseal dysplasia-Maroteaux type (SED-MT, OMIM# 184095). > So far, more than 30 pathogenic genes have been identified to cause SEMD. These disease-causing genes are involved in encoding various types and functions of proteins (Cormier-Daire, 2008). It is difficult to define them as a common signal pathway among all the SEMD. In such clinical and genetic heterogeneous diseases, different gene-disease associations and overlapping clinical characteristics of different genes complicate the differential diagnosis. According to the nosology and classification of genetic skeletal disorders 2019 revision, groups 10-13 are classified as spondylo-epi-metaphyseal abnormalities, but these diseases still exist in other groups (Mortier et al., 2019). The more common SEMD were COL2A1-related dysplasia and pseudoachondroplasia (OMIM# 177170). > At present, most of the reports of SEMD are single case reports, and there are few studies focusing on exploring the phenotype of SEMD caused by different disease-causing genes. We reported seven families with SEMD caused by TRPV4, COL2A1, CCN6, SBDS, and ACAN genes in order to explore the relationship between phenotype and genotype of them. Several studies have reported the phenotype-genotype relations of skeletal disorders caused by COL2A1, COMP, and CCN6 genes (Barat-Houari et al., 2016a;Madhuri et al., 2016;Liang et al., 2021), but we still need more families to prove it, especially Chinese families. Therefore, we summarized the clinical manifestations, radiological data, and molecular features of patients with SEMD, hoping to improve our understanding of Chinese families with SEMD.
  • Snippet 2 (score: 0.566) > Spondylo-epi-metaphyseal dysplasia (SEMD) is a heterogeneous genetic disorder, involving vertebral, epiphyseal, and metaphyseal dysplasia, and is diagnosed based on clinical phenotype, radiographic examination, and molecular sequencing. The primary clinical feature is a different degree of short stature (may present with short limbs or short trunk), combined with specific orthopedic symptoms (such as developmental coxa vara and scoliosis). Epiphyseal dysplasia usually leads to early-onset osteoarthritis, mostly in weightbearing joints (Briggs et al., 1995). Odontoid hypoplasia causes atlantoaxial instability with severe spinal compression problems (Miyoshi et al., 2004). Radiological features included platyspondyly, vertebral body irregularity, destruction of articular cartilage, and dysplasia of epiphysis and metaphysis (Spranger, 1989). > This category of diseases is usually given the nomenclature according to the site name of manifest radiographic abnormalities (Alanay and Lachman, 2011;Mortier et al., 2019) (Figure 1), including spondyloepiphyseal dysplasia (SED), spondylometaphyseal dysplasia (SMD), spondyloepi-metaphyseal dysplasia (SEMD), metaphyseal dysplasia (MD), and epiphyseal dysplasia (ED). With the in-depth study, SEMD is further classified according to specific clinical manifestations. For example, SED with different clinical manifestations can be divided into spondyloepiphyseal dysplasia congenita (SEDC, OMIM# 183900), spondyloepiphyseal dysplasia-Kimberley type (SED-KT, OMIM# 608361), and spondyloepiphyseal dysplasia-Maroteaux type (SED-MT, OMIM# 184095).

[2] X‐linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families

  • Authors: J. Fiedler, M. Merrer, G. Mortier, S. Heuertz, L. Faivre et al.
  • Year: 2004
  • Venue: Human Mutation
  • URL: https://www.semanticscholar.org/paper/252156da9f4936fffde8fe2cbd01c107853b6f4d
  • DOI: 10.1002/humu.9254
  • PMID: 15221797
  • Citations: 25
  • Summary: All sequence variations identified are either deletions of complete exons or predicted to result in a premature stop codon or to lead into splicing defects and are associated with a loss of considerable parts of the sedlin protein.
  • Evidence snippets:
  • Snippet 1 (score: 0.577) > The term spondyloepiphyseal dysplasia (SED) refers to a heterogeneous group of skeletal dysplasias with mainly involvement of the epiphyses and vertebral bodies on radiographs. Patients usually have short stature and early development of degenerative joint disease. SED has been divided into a congenita and a tarda form according to the age of onset and clinical severity. The different modes of inheritance within the group of SEDs reflect the genetic heterogeneity. Autosomal dominant, autosomal recessive and X-linked recessive patterns of inheritance have been described. In autosomal dominant forms of SED congenita (MIM# 183900) (Spranger et al., 1994) and spondyloepimetaphyseal dysplasia (SEMD; MIM# 184250) Strudwick type (Tiller et al., 1995) mutations in the type II collagen gene (COL2A1), the most abundant collagen of cartilage, have been identified. In another autosomal recessive form of SEMD, mutations have been described in the ATPSK2 gene that is involved in sulfation of proteoglycans (ul Haque et al., 1998). > X-linked spondyloepiphyseal dysplasia tarda (SEDT; MIM# 313400) is characterized by moderate short stature, barrel chest deformity and minor epiphyseal abnormalities. The diagnosis is usually made based on the characteristic vertebral body dysplasia comprising platyspondyly and a central hump (Iceton and Horne, 1986;Whyte et al., 1999). Degenerative joint disease is a common problem in male patients making joint replacement of the hips often necessary in the fourth or fifth decade. The gene causing SEDT (SEDL; MIM# 300202; RefSeq ID: NM_014563.2) was mapped to Xp22 (Szpiro-Tapia et al., 1988). The SEDL gene contains 6 exons and spans a genomic region of approximately 20kb.

[3] Novel COL2A1 variants in Japanese patients with spondyloepiphyseal dysplasia congenita

  • Authors: M. Akahira-Azuma, Yumi Enomoto, N. Nakamura, Takayuki Yokoi, Mari Minatogawa et al.
  • Year: 2022
  • Venue: Human Genome Variation
  • URL: https://www.semanticscholar.org/paper/a175a7bef26158a684828ec52f143367c61342d0
  • DOI: 10.1038/s41439-022-00193-x
  • PMID: 35581182
  • PMCID: 9114327
  • Citations: 3
  • Summary: The genotype-phenotype correlations in five Japanese patients with SEDC are reported based on their clinical and radiological findings and it is found that all five patients had novel missense variants resulting in glycine substitutions.
  • Evidence snippets:
  • Snippet 1 (score: 0.535) > . Our five patients also presented with variable nonskeletal complications, suggesting the importance of genetic diagnosis for early intervention and prevention. However, it is difficult to establish clear rules for a genotype-phenotype correlation in SEDC. Other genetic or nongenetic factors could be involved that have not yet been discovered. > In conclusion, genetic testing can provide definitive diagnosis in patients with SEDC. Since the different manifestations may involve not only domain-specific but also codon-specific underlying mechanisms, it would be extremely useful to accumulate information on the correlation between pathogenic variants and clinical features as well as prognosis in these patients. Fig. 1 Clinical and genetic findings of five children with spondyloepiphyseal dysplasia congenita. A Distribution of the six novel COL2A1 variants that were identified. B Growth charts (Japanese version 2020) for Patients 2, 3, and 5. C Skeletal survey for Patient 2. Radiographic findings included significant platyspondyly, shortening of long bones with ragged metaphyses, mild iliac hypoplasia, and delayed ossification of the femur head.

[4] Identification of a New Variant of the MBTPS1 Gene of the Kondo-Fu Type of Spondyloepiphyseal Dysplasia (SEDKF) in a Saudi Patient

  • Authors: Maha Alotaibi, Ali M Aldossari, I. Khan, Leena Alotaibi
  • Year: 2022
  • Venue: Case Reports in Pediatrics
  • URL: https://www.semanticscholar.org/paper/f9b83c984a2c14a5556b0b3648a0c5de8cc5cb55
  • DOI: 10.1155/2022/5498109
  • PMID: 36330313
  • PMCID: 9626241
  • Citations: 3
  • Summary: Considering clinical phenotypes and radiological findings produced by the pathogenic mutation in the MBTPS1 gene, the identified c.2634C > A variant is supported and may be categorized as likely pathogenic based on clinical symptoms.
  • Evidence snippets:
  • Snippet 1 (score: 0.530) > Skeletal dysplasia is a heterogeneous group of bone growth disorder, nonfatal, presented as short stature and skeletal deformities [4]. Clinically and genetically, these disorders vary widely. While some spondyloepiphyseal dysplasia, such as spondyloepiphyseal dysplasia congenita (SEDC), appear during pregnancy, others do so during childhood. > e Kondo-Fu form of spondyloepiphyseal dysplasia SEDKF is one of the rare disorders that come under the umbrella of skeletal dysplasia. One patient with SEDKF was included in our investigation. Short trunk and intellectual impairment are all manifestations of SEDKF. Dysmorphic facial features, kyphosis, pectus carinatum, and bone deformity are further SEDKF symptoms. During the clinical valuation of our patient, including body examination and radiological investigations, we did not manifest bilateral cataract and inguinal hernia. > Membrane-bound transcription factor site-1 protease (MBTPS1) is an enzyme encoded by the MBTPS1 gene in humans. S1P cleaves the transcriptional regulators of the sterol regulatory element-binding protein's endoplasmic reticulum loop (SREBP) [5]. Due to genetic abnormalities in key regulators of the secretory apparatus, MBTPS1-related disorders are a category of hereditary diseases defined by secretion deficits in chondrocytes in cartilage, resulting in skeletal dysplasia and eventual growth retardation. If too much collagen is not released from cells and eventually accumulates within the cells, the skeletal organs can malfunction. > Spondyloepiphyseal dysplasia of the Kondo-Fu type (SEDKF) is a rare autosomal recessive disorder caused by a mutation in the MBTPS1 gene that results in short stature and other phenotypes such as a triangular face, spondyloepiphyseal dysplasia, kyphosis, growth retardation, delayed motor milestones, and elevated lysosomal enzymes.

[5] EndoCompass Project: Research Roadmap for Calcium and Bone Endocrinology

  • Authors: K. Jähn-Rickert, K. Z. Tomsic, A. Anastasilakis, Jean-Philippe Bertocchio, M. L. Brandi et al.
  • Year: 2025
  • Venue: Hormone Research in Pædiatrics
  • URL: https://www.semanticscholar.org/paper/fccbdcae3a86c448632e05f9c38ad2563c14284d
  • DOI: 10.1159/000549160
  • PMID: 41296665
  • PMCID: 12698132
  • Summary: This framework identifies crucial investigation areas into metabolic bone disease pathophysiology, prevention, and treatment strategies, ultimately aimed at reducing the burden of these disorders on individuals and society.
  • Evidence snippets:
  • Snippet 1 (score: 0.527) > Skeletal dysplasias encompass a large spectrum of genetic disorders of the skeleton with abnormal bone growth, structure, or strength [85]. Individually, they are rare but, collectively, due to the large number of skeletal dysplasias (>700), they result in significant morbidity. The underlying pathology remains inadequately understood and the optimal therapy is often undefined, with precision drug treatment targeting the underlying molecular mechanism not available for most skeletal dysplasias. Gene discoveries have increased exponentially, demonstrating the value of advanced genetic tools and motivating further research into the complex pathogenesis of skeletal dysplasias. > However, further basic research is required to uncover the cellular pathology and implicated molecular pathways in various forms of skeletal dysplasia. Understanding the pathophysiology of skeletal dysplasias may also benefit a larger patient population. This is evidenced by anti-sclerostin treatment for osteoporosis [86] which, at present, is in clinical trials for osteogenesis imperfecta. Preclinical data show positive effects on bone mass and strength [87]. > The spectrum of disease manifestations of various skeletal dysplasias in different phases of life and health projections across the life course remain inadequately studied. Research on therapeutic approaches needs to focus not only on correcting the pathophysiology but also, more broadly, on surgical approaches, rehabilitation, functional/environmental adaptations, preventative measures, pain management, psychological support, and quality of life. Patient groups must be involved in identifying these research goals. International registries should be utilized to collect and analyse such data. > A multidisciplinary approach is of particular importance in genetic skeletal disorders, to enable cohesive care throughout the life course. The patients have a range of physical impairments due to their skeletal disorder, but also a disease-specific spectrum of extraskeletal manifestations requiring medical attention. These may include, for example, dental and oral health problems, immune deficiency, impaired hearing, and neurological or ophthalmologic manifestations.

[6] Mutation Update for COL2A1 Gene Variants Associated with Type II Collagenopathies

  • Authors: M. Barat-Houari, G. Sarrabay, V. Gatinois, A. Fabre, B. Dumont et al.
  • Year: 2016
  • Venue: Human Mutation
  • URL: https://www.semanticscholar.org/paper/9ded412dd4d40669a5a4f364f1f7b3c16d67c645
  • DOI: 10.1002/humu.22915
  • PMID: 26443184
  • Citations: 139
  • Influential citations: 7
  • Summary: A review of COL2A1 mutations extracted from the Leiden Open Variation Database (LOVD) that was updated with data from PubMed and patients to provide support and potential collaborative material for scientific and clinical projects aimed at elucidating phenotype–genotype correlation and differential diagnosis in patients with type II collagenopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.518) > Mutations in type II collagen cause a spectrum of autosomaldominant conditions characterized by skeletal dysplasia [Nishimura et al., 2005;Kannu et al., 2011a] (Table 1). Achondrogenesis type II, hypochondrogenesis, and Torrance type platyspondylic dysplasia Additional Supporting Information may be found in the online version of this article. * Correspondence to: Isabelle Touitou, Hôpital Arnaud de Villeneuve, CHRU Montpellier-Université Montpellier 1, INSERM U844, Unité médicale des maladies auto-inflammatoires, 371, av doyen giraud, Montpellier 34295, France. E-mail: > isabelle.touitou@inserm.fr are the most severe phenotypes and are associated with neonatal death. Spondyloepiphyseal dysplasia congenita (SEDC), spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, Kniest dysplasia, spondyloperipheral dysplasia, and Czech dysplasia are phenotypes of intermediate severity. The milder forms encompass early-onset osteoarthritis and Stickler syndrome type I, which is the most frequent type II collagenopathy (1/10,000). The nonlethal diseases may occur at various ages, and early disease onset results in short stature, whereas later onset presents as isolated joint disease or as an ocular phenotype. > The COL2A1 gene (MIM #108300) encodes the alpha 1 chain of procollagen type II. Molecular defects in this gene cause type II collagenopathies Spranger et al., 1994], and genetic diagnosis is routinely provided [Williams et al., 1992;Richards et al., 2006]. An assessment of the clinical significance of COL2A1 variants is critical to providing accurate genetic counseling for affected families. There is no recent COL2A1 mutation review article in the literature. Here, we provide an exhaustive description of the mutations found in this gene from all available sources, including PubMed, online databases, and our own data [

[7] Novel COL2A1 variants in Japanese patients with spondyloepiphyseal dysplasia congenita

  • Authors: M. Akahira-Azuma, Yumi Enomoto, N. Nakamura, Takayuki Yokoi, Mari Minatogawa et al.
  • Year: 2022
  • Venue: Human Genome Variation
  • URL: https://www.semanticscholar.org/paper/814f10a15fefd149f067b4c28959d955ab66c93e
  • DOI: 10.1038/s41439-022-00193-x
  • Summary: The genotype-phenotype correlations in five Japanese patients with SEDC based on their clinical and radiological findings suggest novel missense variants resulting in glycine substitutions are important for early intervention for the extraskeletal complications of S EDC.
  • Evidence snippets:
  • Snippet 1 (score: 0.517) > Spondyloepiphyseal dysplasia congenita (SEDC) is a multisystemic skeletal disorder caused by pathogenic variants in COL2A1. Here, we report the genotype-phenotype correlations in five Japanese patients with SEDC based on their clinical and radiological findings. All five patients had novel missense variants resulting in glycine substitutions (G474V, G543E, G567S, G594R, and G1170R). Genetic testing is important for early intervention for the extraskeletal complications of SEDC. Spondyloepiphyseal dysplasia congenita (SEDC) (OMIM#183900) is an autosomal dominant chondrodysplasia characterized by disproportionate short stature, abnormal epiphyses, flattened vertebral bodies (skeletal abnormalities), and extraskeletal features, including myopia, retinal degeneration with retinal detachment, and cleft palate. SEDC is caused by a heterozygous variant in the collagen II alpha 1 (COL2A1) gene.

[8] Diagnostic Challenge of Phenotypic Variability in COL2A1-related Disorders: Four Novel Variants That Expand the Clinical Spectrum

  • Authors: Burcu Yeter, Y. Demirkol, Metin Eser, A. H. Akgülle, B. Sözeri et al.
  • Year: 2025
  • Venue: Journal of Clinical Research in Pediatric Endocrinology
  • URL: https://www.semanticscholar.org/paper/64e575d805d829f26319a1cde6343dff23f9b720
  • DOI: 10.4274/jcrpe.galenos.2025.2024-9-7
  • PMID: 39849673
  • PMCID: 12372628
  • Citations: 1
  • Summary: The clinical, radiological, and molecular findings of patients with COL2A1-related dysplasia are described and the phenotype-genotype correlation is investigated to investigate the phenotype-genotype correlation.
  • Evidence snippets:
  • Snippet 1 (score: 0.503) > Objective Heterozygous COL2A1 gene mutations are associated with type 2 collagenopathies, characterized by a wide, diverse, and overlapping clinical spectrum in related diseases. Our goal is to describe the clinical, radiological, and molecular findings of patients with COL2A1-related dysplasia and investigate the phenotype-genotype correlation. We also highlight the challenge of categorizing COL2A1-related diseases with similar clinical and radiological phenotypes. Methods Six patients from five unrelated families presented with disproportionate short stature.delayed motor milestones, waddling gait, normal intelligence, and similar radiological features, including delayed epiphyseal ossification, epimetaphyseal changes, scoliosis, lordosis, and platyspondyly. All underwent whole exome sequencing. Demographic, clinical, laboratory, and radiological data were retrospectively obtained from hospital records. Segregation analysis was conducted using Sanger sequencing in all patients. Results Based on clinical, radiological, and molecular results, the six patients were categorized into kniest dysplasia, spondyloepiphyseal dysplasia congenita, and spondyloepimetaphyseal dysplasia Strudwick type. Four novel variants (c.1023+2T>C, p.Gly465Asp, p.Gly855Asp, p.Gly669Ala) were identified in the COL2A1 gene. Conclusion Accurate classification of type 2 collagenopathies is vital to provide appropriate genetic counseling. Predicting extraskeletal manifestations and reducing morbidity through early diagnosis and treatment will significantly improve the quality of life for patients.
  • Snippet 2 (score: 0.453) > The disease spectrum ranges from only osteoarthritis with normal stature or ocular complications and hearing loss to severe micromelia, dwarfism, and perinatal lethality. Achondrogenesis type 2 (ACG2) or hypochondrogenesis (HCG) and platyspondylic skeletal dysplasia Torrance type are perinatal lethal forms; kniest dysplasia (KD), spondyloepiphyseal dysplasia congenita (SEDC), spondyloepimetaphyseal dysplasia (SEMD) Strudwick type, spondyloepiphyseal dysplasia Stanescu type and spondyloperipheral dysplasia are moderate forms; epiphyseal dysplasia multiple with myopia and deafness, vitreoretinopathy with phalangeal epiphyseal dysplasia, avascular necrosis of the femoral head, Czech dysplasia, Legg-Calve-Perthes disease, osteoarthritis with mild chondrodysplasia, Stickler syndrome type 1 (STL1), and non-syndromic ocular STL1 are mild forms (4). While the overall prevalence remains unknown, the estimated incidence worldwide ranges from 20.4 to 35.9/100,000 across various locations and populations (5). Due to COL2A1 mutations leading to different phenotypes, even within the same family, clinical variability is observed. > In general, when type 2 collagenopathies are mentioned, the first things that come to mind are short trunk dwarfism, eye involvement (myopia and vitreoretinal detachment), hearing loss, and joint pain. Cleft palate, midface hypoplasia, and micrognathia may also be considered dysmorphic facial features. Radiographic manifestations include platyspondyly, irregular vertebral endplates, kyphosis, lordosis, delayed epiphyseal ossification, and epimetaphyseal changes.

[9] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 37
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.496) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[10] Skeletal Dysplasias Caused by Sulfation Defects

  • Authors: Chiara Paganini, Chiara Gramegna Tota, A. Superti-Furga, A. Rossi
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/e455f358a08f6e9fc09ef5f2d3751d11e9145e92
  • DOI: 10.3390/ijms21082710
  • PMID: 32295296
  • PMCID: 7216085
  • Citations: 25
  • Influential citations: 1
  • Summary: A panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation is presented, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.
  • Evidence snippets:
  • Snippet 1 (score: 0.491) > Over the last few years, there have been significant advances in the skeletal dysplasia field leading to the identification of the underlying genetic defects in more than 400 different skeletal disorders [15]. The above synopsis highlights the complexity of skeletal defects caused by mutations in genes encoding for enzymes and transporters involved in sulfate metabolism. Progress in this field has been allowed by next-generation genomic technologies, that are a first-line diagnostic resource. In this complex scenario, patient derived biopsies, cell cultures, and animal models are fundamental to investigate the pathogenesis and to analyze new aspects of the role of GAG in connective tissue biology. > Despite the great step forward in the identification of causative genes, genotype-phenotype correlations are lacking and we are still far from a comprehensive view of the disease molecular mechanisms. First, it is unclear how the tissue specificity and the redundancy of genes can determine the phenotype. Defects in PG sulfation mainly affect cartilage and bone, but other tissues can be involved as cardiac tissue in SEDCJD [82,84] or lymphoid tissue leading to tumour progression in OCBMD [91]. The involvement of different tissues and its implications on the disease phenotype should be carefully studied in the future. Moreover, mutations in different genes cause skeletal dysplasias with overlapping features that may be wrongly diagnosed as occurs in condrodysplasia with joint dislocation, gPAPP type, Catel-Manzke syndrome and Desbuquois dysplasia type 1. Nowadays we cannot provide a full explanation why some classes of sulfated PGs are more affected by enzyme deficiency than others. Even if the GAGs role depends on their physicochemical properties, it is difficult to molecularly dissect the function of sulfated GAGs when they interact in the complex ECM network. Lastly, the variability in the clinical phenotypes caused by mutations in the same gene suggests that also environmental and epigenetic factors might play a role. > A deep understanding of the molecular mechanisms of these disorders is crucial to ultimately pave the way for innovative therapies.

[11] TRPV4: A Physio and Pathophysiologically Significant Ion Channel

  • Authors: T. Rosenbaum, Miguel Benítez-Angeles, Raúl Sánchez-Hernández, S. Morales-Lázaro, M. Hiriart et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/09943959f11255605b780fc692ef57a0cc9ef945
  • DOI: 10.3390/ijms21113837
  • PMID: 32481620
  • PMCID: 7312103
  • Citations: 105
  • Influential citations: 3
  • Summary: Several lines of evidence derived from animal models and even clinical trials in humans highlight TRPV4 as a therapeutic target and as a protein that will receive even more attention in the near future, as will be reviewed here.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Certain diseases were previously thought to be distinct clinical phenotypes until it was discovered that there was a common underlying molecular basis: their association with the mutations and malfunction of TRPV4 (Figure 5). Presently, these disorders have been grouped into skeletal dysplasias (metatropic dysplasia, parastremmatic dysplasia, Maroteaux type spondyloepiphyseal dysplasia, Kozlowski type spondyloepiphyseal dysplasia (SMDK), autosomal dominant brachyolmia, familial digital arthropathy-brachydactyly), and into neuromuscular disorders (congenital distal spinal muscular atrophy, scapuloperoneal spinal muscular atrophy, Charcot-Marie-Tooth disease type 2C), which vary in severity. Skeletal dysplasias exhibit brachydactyly (shortness of fingers and toes), and depending on the severity of the disease, there is also short stature and spinal deformity, the pelvis, and long bones, which can also be affected, and sometimes the life span of the individuals is reduced. On the other hand, neuromuscular disorders present themselves with respiratory dysfunction, joint contractures, and progressive peripheral neuropathy [182]. > All of these diseases, which are grouped into two large categories (i.e., neuromuscular disease and skeletal dysplasia), encompass progressive degeneration of peripheral nerves or lack of establishment and development of the hard-skeletal tissues. > It had been previously shown that inactivation missense mutations in the PkdI (polycystic kidney disease) gene that encodes the polycystin-1 (PC1) membrane protein led to tardy intramembranous and endochondral bone formation in a mutant mice (Pkd1 mlBei ) strain [183]. A link between this discovery and the role of TRPV4 in the skeletal system was later made since it had been shown that PC1 activates TRPV4 through a G-protein coupled receptor (GPCR) mechanism [184].

[12] Non-Invasive Prenatal Screening for Down Syndrome: A Review of Mass-Spectrometry-Based Approaches

  • Authors: Răzvan Lucian Jurca, I. Pralea, M. Iacobescu, I. Rus, C. Iuga et al.
  • Year: 2025
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/77585fbeddaee796b0d9030dfccee9713f2d3e52
  • DOI: 10.3390/life15050695
  • PMID: 40430124
  • PMCID: 12112985
  • Citations: 1
  • Summary: A comprehensive examination of the differentially expressed proteins (DEPs) and metabolites (DEMs) reported in the literature in T21 prenatal screening aims to guide future research in the field and foster the development of more advanced, less invasive prenatal screening techniques for T21.
  • Evidence snippets:
  • Snippet 1 (score: 0.484) > Additionally, CS and DS are commonly associated with atherosclerosis, nerve development and repair, inflammation, tumor growth, and metastasis [80]. Modifications of the enzymes involved in the biosynthesis of glycosaminoglycans are important in Ehlers-Danlos syndrome, joint dislocations, short stature, spondyloepiphyseal dysplasia with congenital joint dislocations, spondyloepimetaphyseal dysplasia with joint laxity type 1, congenital heart defects, and Temtamy preaxial brachydactyly syndrome. While congenital heart defects and joint laxity are common in T21 patients, the co-occurrence of T21 and Ehlers-Danlos syndrome is rare, and no established correlation exists between the two conditions [104]. > Pathways associated with diseases of hemostasis were predominantly observed in maternal plasma, along with pathways related to signal transduction mediated by growth factors and second messengers-specifically, oncogenic MAPK signaling. MAPKs are protein kinases that control intracellular processes, such as gene expression, metabolism, proliferation, differentiation, and apoptosis, as part of normal physiology, being mainly studied in the context of oncogenesis, tumor progression, and drug resistance [105]. MAPK pathways in T21 patients have been primarily studied to enhance antitumor treatment efficacy in patients with B cell acute lymphoblastic leukemia [106] or to assess MAPK activity in the brains of T21 and Alzheimer's disease patients [107]. > Table 2 summarizes the key molecular pathways implicated in Down syndrome (T21), emphasizing their normal biological functions and the observed or potential alterations in T21. While direct evidence for some pathways remains limited, numerous pathways-particularly those involved in signaling, immune functions, extracellular matrix organization, and metabolic processes-show promising associations with the clinical features of T21. Regarding the metabolomic pathways of significant differentially expressed metabolites (DEMs) in T21, brief discussions on this topic are included in the description of each metabolomic study outlined in the previous section.

[13] Spondyloepiphyseal dysplasia congenita

  • Authors: Y. Glick
  • Year: 2020
  • Venue: Definitions
  • URL: https://www.semanticscholar.org/paper/5c85234647b055c18b8374c50050dab900ffd7b3
  • DOI: 10.1007/978-3-540-29676-8_6867
  • Citations: 67
  • Summary: People with spondyloepiphyseal dysplasia congenita have short stature from birth, with a very short trunk and neck and shortened limbs. Their hands and feet, however, are usually average-sized. Adult height ranges from 3 feet to just over 4 feet. Abnormal curvature of the spine (kyphoscoliosis and lordosis) becomes more severe during childhood. Instability of the spinal bones (vertebrae) in the neck may increase the risk of spinal cord damage. Other skeletal features include flattened vertebr...
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > Spondyloepiphyseal dysplasia congenita

[14] A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

  • Authors: M. Formosa, D. Bergen, C. Gregson, A. Maurizi, A. Kämpe et al.
  • Year: 2021
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/be13ff3ea01dc5719f2c63b2cbf5d9f77bafd659
  • DOI: 10.3389/fendo.2021.709711
  • PMID: 34539568
  • PMCID: 8444146
  • Citations: 21
  • Summary: The monogenic forms of rare low and high rare bone Mass disorders known to date are described, a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders is provided, using proper phenotyping and genotyping methods are provided, and different genetic validation approaches paving the way for future treatments are described.
  • Evidence snippets:
  • Snippet 1 (score: 0.476) > Skeletal development is regulated by numerous genetic factors that guide the growth, modeling and remodeling of skeletal structures starting in early fetal development and continuing throughout life. These processes are crucial for attainment of normal height, skeletal patterning, bone shape, and mobility, but also for maintenance of normal bone mass and fracture resistance. Defects in the involved genes result in a large and heterogeneous group of disorders, collectively called skeletal dysplasias, in which the primary features are confined to the skeleton. More than 460 different forms of skeletal dysplasia, most of them monogenic, have been recognized (1). They are estimated to affect approximately 1/5,000 children (2,3), and can have distinct clinical manifestations and course. Clinical outcomes range in severity from neonatal lethality to only mild growth retardation, deformity or fracture risk. Diagnosis is based on growth pattern and other clinical characteristics, skeletal imaging, bone density testing, biochemical diagnostics, and genetic tests. Although the genetic basis has been described and mutations in the responsible genes identified in a significant proportion of these conditions, for several distinct skeletal dysplasia phenotypes the genetic cause is still not known (1). > Within this large group of genetic skeletal disorders, monogenic disorders affecting bone mass comprise an expanding subgroup (1,4). This includes disorders with low bone mass and skeletal fragility, and disorders leading to increased bone mass, both commonly associated with extraskeletal complications (5,6). Due to significant variability in severity, diagnosis can be challenging. Importantly, the underlying molecular genetic mechanisms for these disorders remain inadequately explored and, in several entities, the causative genetic defect, and underlying cellular and molecular pathophysiology are still uncharacterized. > The various skeletal dysplasia delineated to date have provided important information about the molecular pathways governing skeletal health both in these conditions and in the general population, underscoring the significance of new gene discoveries not only for the individuals affected by the monogenic rare bone mass disorder, but also more widely to the musculoskeletal research field (7). Indeed, the large wealth of data generated from monogenic and polygenic bone mass disorders, frailty and other musculoskeletal traits, have led

[15] A novel type II collagen gene mutation in a family with spondyloepiphyseal dysplasia and extensive intrafamilial phenotypic diversity

  • Authors: Y. Nakashima, Y. Sakamoto, G. Nishimura, S. Ikegawa, Y. Iwamoto
  • Year: 2016
  • Venue: Human Genome Variation
  • URL: https://www.semanticscholar.org/paper/319ca8291900c74c780bf0a97de3f32ec8ef6f61
  • DOI: 10.1038/hgv.2016.7
  • PMID: 27274858
  • PMCID: 4871930
  • Citations: 7
  • Summary: A family with spondyloepiphyseal dysplasia caused by a novel type II collagen gene (COL2A1) mutation and the family’s phenotypic diversity was described, finding Phenotypes were diverse even among individuals with the same mutation and within the same family.
  • Evidence snippets:
  • Snippet 1 (score: 0.458) > More than 400 COL2A1 mutations have been reported in the Human Gene Mutation Database (https://portal.biobase-international.com/hgmd/), and these mutations result in a diverse phenotypic spectrum that predominantly affects cartilage and bone. 3,4 On the basis of clinical findings, type II collagenopathies are divided into several categories, including spondyloepiphyseal dysplasia (SED) spectrum, Stickler dysplasia type I and Kniest dysplasia. 5,6 The SED spectrum is further divided into several phenotypes. 3 Achondrogenesis type II and hypochondrogenesis are lethal and at the severe end of this spectrum. SED congenita is characterized by short stature with a short trunk and coxa vara. SED tarda indicates late-onset SED. The distinction among the SED spectrum phenotypes is mainly based on clinical features; however, considerable phenotypic diversity often hampers proper classification even with the same mutation. 5 In the present study, we describe a Japanese family with SED caused by a novel COL2A1 mutation. This mutation predominantly affected the hip joint and spine of the affected individuals in this family. In addition, extensive intrafamilial phenotypic diversity was observed. > This study was approved by the local Institutional Review Board, and informed consent was obtained from all participants. > The index case (case 4) was a 50-year-old female with bilateral hip pain during her initial examination. Plain radiographs showed joint space narrowing without acetabular dysplasia and atlantoaxial subluxation and platyspondyly in her thoracolumbar spine (Figure 1a-c). She was diagnosed with SED. Her family members also exhibited below average height, and/or spine and joint symptoms. Their pedigree is shown in Figure 2a. The patient's skeletal problems seemed to be an inherited autosomal dominant trait; thus, we performed clinical and molecular surveys on seven affected members (cases 1-4 and 6-8) and one normal member (case 5) of her family. Table 1 is a summary of clinical and radiographic findings from the family. The stature of affected members ranged from extremely short to

[16] Galactosialidosis: A Report of Three Cases Diagnosed With a Founder Genetic Mutation in the Bahraini Population

  • Authors: Z. Alsahlawi, Zahraa J. Alhadi, E. Abdulla, Sara H Ebrahim, Manal M Alshehab et al.
  • Year: 2025
  • Venue: Cureus
  • URL: https://www.semanticscholar.org/paper/9e8abc846c9856fa0473c83ff0ca8dc2d21aed56
  • DOI: 10.7759/cureus.77750
  • PMID: 39981487
  • PMCID: 11840274
  • Citations: 1
  • Summary: Three newly diagnosed cases of late-infantile GS in Bahraini patients, all sharing the same previously reported homozygous mutation in the CTSA gene are presented, reflecting a founder effect in the Bahraini population.
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > Chest X-ray was normal, and lumbosacral spine imaging was suggestive of spondyloepiphyseal dysplasia congenita. A bone mineral density scan of the hands showed normal texture and density for her age. > Two years later, a magnetic resonance imaging (MRI) of the pelvis revealed bilateral significant flattening of the femoral capital epiphysis, which was symmetrical with dysplastic features of the hip. While these findings simulated Perthes disease, bone dysplasia and the possibility of spondyloepiphyseal dysplasia with mucopolysaccharidosis were considered more likely. > Laboratory investigations, including hormonal assays, were normal. A screening test for urinary glycosaminoglycans (GAGs) was sent to Frankfurt, Germany, with results showing a normal GAG pattern, thus excluding all types of mucopolysaccharidosis except MPS type IV (Morquio syndrome), which could not definitely be excluded based on clinical and radiological findings. > Further investigations, including ophthalmology and cardiology reviews, were suggested but not completed, as the patient lost follow-up after the age of 15 years. Additionally, scanogram images of the lower Based on the clinical presentation, laboratory results, skeletal findings, and a positive mutation in her younger brother for GS, the patient was called to attend the metabolic and genetic clinic. At the age of 28 years, coinciding with her brother's diagnosis of GS in the same year, the diagnosis of GS for her was confirmed through targeted mutation analysis using polymerase chain reaction. This genetic testing identified a homozygous mutation in the CTSA gene (c.607C>A, p.Pro203Thr). > The patient is currently stable, with no significant complications other than skeletal deformities and difficulty walking long distances, accompanied by back pain. Genetic counseling was given to the family about the risk of recurrence, other siblings have not been tested for the familial variant as they clearly do not have any symptoms related to the disease.

[17] Specific heterozygous variants in MGP lead to endoplasmic reticulum stress and cause spondyloepiphyseal dysplasia

  • Authors: O. Gourgas, G. Lemire, Alison J. Eaton, Sultanah Alshahrani, A. Duker et al.
  • Year: 2023
  • Venue: Nature Communications
  • URL: https://www.semanticscholar.org/paper/6f3fb0c824daec40f303c94dede4c9a8f28e13ad
  • DOI: 10.1038/s41467-023-41651-6
  • PMID: 37923733
  • PMCID: 10624854
  • Citations: 9
  • Summary: It is reported that heterozygous missense variants affecting one particular cysteine residue of MGP can cause a clinically distinct, dominant disorder, likely via impaired signal peptide processing leading to cellular stress and apoptosis.
  • Evidence snippets:
  • Snippet 1 (score: 0.447) > Exome sequencing combined with a one-sided matchmaking strategy resulted in the identification of four individuals from two unrelated families with a heterozygous variant in MGP affecting the same highly conserved cysteine (Cys 19) residue. These individuals presented with a strikingly overlapping spondyloepiphyseal dysplasia phenotype, which was distinct from that of individuals with KS caused by biallelic loss-of-function variants in MGP 11 . Platyspondyly and progressive epiphyseal degeneration were significant in the four affected individuals in this report which were not described in patients with KS. Also, pulmonary artery stenosis, arterial calcification, hearing loss, and developmental delay are common clinical features in KS and were not present in the individuals from this cohort 8,[18][19][20] . Nonetheless, there were a few notable phenotypic similarities between the current cohort of affected individuals and KS patients. Radiographs of the hands of affected individuals demonstrated brachytelephalangism of the lesser digits, which is seen in KS. Midface retrusion is also a clinical feature observed in individuals with KS 11,21 and was seen in our cohort, especially in Individual 4 carrying the 56G>A variant. In addition, Individual 4 did appear to have premature calcification of the cricoid cartilage, albeit not as significant as the vast tracheal ring calcifications seen in KS. Short stature has also been reported in individuals with KS 10,18 . Despite these similarities, the defining features of the affected individuals with heterozygous 56G>T or 56G>A variants in MGP, the vertebral and epiphyseal anomalies, make the condition clinically distinct from KS. We suggest naming this condition Spondyloepiphyseal dysplasia (SED), MGP type. Reporting of additional affected individuals in future will improve the clinical delineation of SED, MGP type. > The identification of novel MGP variants affecting the same cysteine residue in individuals with a previously unreported skeletal disorder and their autosomal dominant mode of inheritance demanded a thorough investigation into the underlying cell and molecular mechanisms.

[18] Signaling Pathways in Bone Development and Their Related Skeletal Dysplasia

  • Authors: Alessandra Guasto, V. Cormier-Daire
  • Year: 2021
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/c5466b45e1a7e5aa8e7ad05c7d9287a9e84e9262
  • DOI: 10.3390/ijms22094321
  • PMID: 33919228
  • PMCID: 8122623
  • Citations: 51
  • Summary: The principal signaling pathways involved in bone development and their associated skeletal dysplasia are reviewed and genotype–phenotype correlations have helped to elucidate their role in skeletogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > In this review, we discussed the main signaling pathways involved in bone development and how mutations in their components have been associated with SD. It is important to highlight that even if the signaling pathways have been discussed independently, there is a complex cross-talk among them at multiple levels. This, in association with the evidence that the mutation consequences depend on the specificity of the mutations and on their temporal and spatial mode of action, makes more difficult the understanding of the physiopathological mechanisms of these diseases. Moreover, these signaling pathways can be secondarily affected by alterations in other cellular processes, such as extracellular matrix regulation or metabolic processing. Indeed, several skeletal dysplasia, that we decided to omit in this review, have been associated with mutations in these processes. Fortunately, in the last decade, the development of new technologies, like whole exome and genome sequencing has accelerated the identification of skeletal dysplasia-causing mutations. On the other hand, the development of CRISPR-Cas9 technology and of several mouse models is helping the deciphering of the physiopathological mechanisms. Advanced genetic testing is also helping the diagnosis of skeletal dysplasia. The diagnosis and management of these pathologies have long been based on clinical feature and skeletal imaging. Today, these key techniques are increasingly combined with the genetic testing in order to obtain a more accurate and early diagnosis of SD. It also aids in prognosis and in counselling families regarding genetic recurrence risk and preconceptional reproductive planning [212][213][214]. These continuous discoveries will help to expand the genotype-phenotype correlation of SD and to develop new therapeutic strategies. Nowadays, few treatments are available for SD, but several clinical trials are ongoing to validate new drugs targeting specifically these pathways in achondroplasia or FOP for example, and highlighting the importance of multidisciplinary cross talks (from bed to bench side) [215].

Notes

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