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Annals of Pediatric Endocrinology &... Dec 2015Skeletal dysplasia (SD) is a kind of heterogeneous genetic disorder characterized by abnormal growth, development, differentiation, and maintenance of the bone and... (Review)
Review
Skeletal dysplasia (SD) is a kind of heterogeneous genetic disorder characterized by abnormal growth, development, differentiation, and maintenance of the bone and cartilage. The patients with SD most likely to be seen by a pediatrician or orthopedic surgeon are those who present with short stature in childhood. Because each category has so many diseases, classification is important to understand SD better. In order to diagnose a SD accurately, clinical and radiographic findings should be evaluated in detail. In addition, genetic diagnosis of SD is important because there are so various SDs with complex phenotypes. To reach an exact diagnosis of SDs, cooperative approach by a clinician, a radiologist and a geneticist is important. This review aims to provide an outline of the diagnostic approach for children with disproportional short stature.
PubMed: 26817005
DOI: 10.6065/apem.2015.20.4.187 -
Molecular Syndromology May 2019TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in are known to cause both a... (Review)
Review
TRPV4, a nonselective calcium permeable ion channel, is expressed broadly in many organs including bone and neurons. Pathogenic variants in are known to cause both a spectrum of skeletal dysplasias and neuropathies. Recent publications have documented a few patients who have a combined phenotype of skeletal dysplasia and neuropathy secondary to pathogenic variants. We present an additional patient who has an overlapping neuromuscular and skeletal phenotype secondary to a pathogenic variant. The patient has spondylometaphyseal dysplasia-Kozlowski type and Charcot-Marie-Tooth disease type 2C. This and prior reports illustrate that -related skeletal dysplasias and -related neuropathies are not fully distinct disorders secondary to unique sets of pathogenic variants as originally postulated, but rather are 2 phenotypes on the same spectrum that may or may not overlap. We suggest that evaluation for patients presenting with any -related disorder include assessment for both skeletal and neurological findings.
PubMed: 31191204
DOI: 10.1159/000495778 -
International Journal of Biological... 2020-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular...
-related disorders represent a heterogeneous group of skeletal dysplasias with a wide phenotypic spectrum. Our aim is to characterize the clinical and molecular phenotypes of Chinese patients with -related dysplasia and to explore their phenotype-genotype relations. Clinical data were collected, physical examinations were conducted, and X-ray radiography and genetic analyses were performed in ten families involving 29 patients with -related dysplasia. Nine mutations were identified in , including five novel (c.816+6C>T, p.Gly246Arg, p.Gly678Glu, p.Gly1014Val and p.Ter1488Gln) and four reported previously (p.Gly204Val, p.Arg275Cys, p.Gly504Ser and p.Arg719Cys). Based on clinical features and molecular mutations, the ten families were classified into five definite -related disorders: four families with spondyloepiphyseal dysplasia congenita (SEDC), three with osteoarthritis with mild chondrodysplasia (OSCPD), one with Czech dysplasia, one with Kniest dysplasia, and one with epiphyseal dysplasia, multiple, with myopia and deafness (EDMMD). Based on genetic testing results, prenatal diagnosis and genetic counseling were accomplished for one female proband with OSCDP. Chinese patients with OSCDP, Czech dysplasia and EDMMD caused by mutations were first reported, expanding the spectrum of mutations and the phenotype of -related disorders and providing further evidence for the phenotype-genotype relations, which may help improve procreative management of -related disorders.
Topics: Adolescent; Adult; Aged; Asian People; Child; Child, Preschool; Cleft Palate; Collagen Diseases; Collagen Type II; Dwarfism; Face; Female; Genotype; Humans; Hyaline Membrane Disease; Male; Middle Aged; Mutation; Osteoarthritis; Osteochondrodysplasias; Phenotype; Toes; Young Adult
PubMed: 32071555
DOI: 10.7150/ijbs.38811 -
Annales de Pathologie Jun 2023Compared to the general population, patients with inflammatory bowel disease (IBD), both ulcerative colitis (UC) or Crohn's disease (CD), are at increased risk of... (Review)
Review
Compared to the general population, patients with inflammatory bowel disease (IBD), both ulcerative colitis (UC) or Crohn's disease (CD), are at increased risk of developing some cancers, particularly colorectal cancers (CRC). CRCs, the vast majority of which are adenocarcinomas, develop from a precancerous lesion called dysplasia (or intraepithelial neoplasia) via an inflammation-dysplasia-adenocarcinoma sequence. The advancements of new endoscopic techniques, including visualisation and resection techniques, has led to a reclassification of dysplasia lesions into visible and invisible lesions and their therapeutic management, with a more conservative approach to the colorectal setting. In addition, besides conventional dysplasia, of intestinal phenotype, classically described in IBD, non-conventional dysplasias (as opposed to conventional dysplasia of intestinal phenotype) are now described, including at least seven subtypes. Recognition of these unconventional subtypes, which are still poorly known from pathologists, is becoming crucial, as some of these subtypes appear to be at high risk of developing advanced neoplasia (i.e. high-grade dysplasia or CRC). This review briefly describes the macroscopic features of dysplastic lesions in IBD, as well as their therapeutic management, followed by the clinicopathological features of these dysplastic lesions, with particular emphasis on the new subtypes of unconventional dysplasia, both from a morphological and molecular point of view.
Topics: Humans; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Carcinoma in Situ; Hyperplasia; Carcinoma; Colorectal Neoplasms
PubMed: 36906454
DOI: 10.1016/j.annpat.2023.02.006 -
ELife Feb 2023Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain...
Mutations in the TRPV4 ion channel can lead to a range of skeletal dysplasias. However, the mechanisms by which TRPV4 mutations lead to distinct disease severity remain unknown. Here, we use CRISPR-Cas9-edited human-induced pluripotent stem cells (hiPSCs) harboring either the mild V620I or lethal T89I mutations to elucidate the differential effects on channel function and chondrogenic differentiation. We found that hiPSC-derived chondrocytes with the V620I mutation exhibited increased basal currents through TRPV4. However, both mutations showed more rapid calcium signaling with a reduced overall magnitude in response to TRPV4 agonist GSK1016790A compared to wildtype (WT). There were no differences in overall cartilaginous matrix production, but the V620I mutation resulted in reduced mechanical properties of cartilage matrix later in chondrogenesis. mRNA sequencing revealed that both mutations up-regulated several anterior genes and down-regulated antioxidant genes and throughout chondrogenesis. BMP4 treatment up-regulated several essential hypertrophic genes in WT chondrocytes; however, this hypertrophic maturation response was inhibited in mutant chondrocytes. These results indicate that the TRPV4 mutations alter BMP signaling in chondrocytes and prevent proper chondrocyte hypertrophy, as a potential mechanism for dysfunctional skeletal development. Our findings provide potential therapeutic targets for developing treatments for TRPV4-mediated skeletal dysplasias.
Topics: Humans; Chondrocytes; Induced Pluripotent Stem Cells; TRPV Cation Channels; Osteochondrodysplasias; Cell Differentiation; Mutation; Hypertrophy; Chondrogenesis
PubMed: 36810131
DOI: 10.7554/eLife.71154 -
Postepy Higieny I Medycyny... Oct 2015Various forms of bony deformations and dysplasias are often present in the facial skeleton. Bone defects can be either localized or general. Quite often they are not... (Review)
Review
Various forms of bony deformations and dysplasias are often present in the facial skeleton. Bone defects can be either localized or general. Quite often they are not only present in the skull but also can be found in other parts of the skeleton. In many cases the presence and levels of specific bone markers should be measured in order to fully describe their activity and presence in the skeleton. Fibrous dysplasia (FD) is the most common one in the facial skeleton; however, other bone deformations regarding bone growth and activity can also be present. Every clinician should be aware of all common, rare and uncommon bony diseases and conditions such as cherubism, Paget's disease, osteogenesis imperfecta and others related to genetic conditions. We present standard (calcium, parathyroid hormone, calcitonin, alkaline phosphatase, vitamin D) and specialized bone markers (pyridinium, deoxypyridinium, hydroxyproline, RANKL/RANK/OPG pathway, growth hormone, insulin-like growth hormone-1) that can be used to evaluate, measure or describe the processes occurring in craniofacial bones.
Topics: Biomarkers; Bone and Bones; Calcium; Cherubism; Clinical Chemistry Tests; Craniofacial Abnormalities; Humans; Osteitis Deformans; Osteogenesis Imperfecta
PubMed: 26561843
DOI: 10.5604/17322693.1176768 -
Annual Review of Pathology Jan 2017Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common... (Review)
Review
Focal cortical dysplasias (FCDs) are malformations of cortical development (MCDs) that are highly associated with medication-resistant epilepsy and are the most common cause of neocortical epilepsy in children. FCDs are a heterogeneous group of developmental disorders caused by germline or somatic mutations that occur in genes regulating the PI3K/Akt/mTOR pathway-a key pathway in neuronal growth and migration. Accordingly, FCDs are characterized by abnormal cortical lamination, cell morphology (e.g., cytomegaly), and cellular polarity. In some FCD subtypes, balloon cells express proteins typically seen in neuroglial progenitor cells. Because recurrent intractable seizures are a common feature of FCDs, epileptogenic electrophysiological properties are also observed in addition to local inflammation. Here, we will summarize the current literature regarding FCDs, addressing the current classification system, histopathology, molecular genetics, electrophysiology, and transcriptome and cell signaling changes.
Topics: Animals; Humans; Malformations of Cortical Development; Molecular Targeted Therapy; Mutation; Signal Transduction
PubMed: 28135561
DOI: 10.1146/annurev-pathol-052016-100138 -
HNO Jun 2020Malformations of the ear are the most common dysplasias in childhood. Ear malformations are classified into dysplasias of the auricle, of the ear canal, and of the... (Review)
Review
Malformations of the ear are the most common dysplasias in childhood. Ear malformations are classified into dysplasias of the auricle, of the ear canal, and of the middle and inner ear. The latter types are fortunately relatively rare. Most common is a low-grade dysplasia of the auricle (otapostasis, cup ear). Higher-grade dysplasia of the auricle (microtia II-III) is often associated with syndromes and/or malformations of the ear canal and the middle ear (e.g., congenital aural atresia with high-grade microtia and dysplasia of the middle ear). Functional aspects of hearing and acquisition of language as well as aesthetic aspects emphasize the importance of surgical therapy. Due to the importance of correctly scheduling surgical treatment in early childhood, this article gives an overview of the possibilities for aesthetic reconstruction of the auricle and the frequently associated functional rehabilitation of hearing.
Topics: Child; Congenital Microtia; Ear Auricle; Ear Canal; Ear, Middle; Hearing; Humans; Plastic Surgery Procedures
PubMed: 32130456
DOI: 10.1007/s00106-020-00831-2 -
Radiographics : a Review Publication of... May 2023Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These...
Skeletal dysplasias are a heterogeneous collection of genetic disorders characterized by bone and cartilage abnormalities, and they encompass over 400 disorders. These disorders are rare individually, but collectively they are common (approximate incidence of one in 5000 births). Radiologists occasionally encounter skeletal dysplasias in daily practice. In the 1980s, Professor Juergen Spranger proposed a concept suitable for the diagnosis of skeletal dysplasias termed He stated that different bone dysplasias that share a similar skeletal pattern can be grouped into a "family," the final diagnosis is feasible through the provisional recognition of a pattern followed by a more careful analysis, and families of bone dysplasias may be the result of similar pathogenetic mechanisms. The prototypes of bone dysplasia families include dysostosis multiplex family, achondroplasia family, spondyloepiphyseal dysplasia congenita family, and Larsen syndrome-otopalatodigital syndrome family. Since Spranger's proposal, the concept of bone dysplasia families, along with advancing genetic techniques, has been validated and further expanded. Today, this molecularly proven concept enables a simple stepwise approach to be applied to the radiologic diagnosis of skeletal dysplasias. The first step is the categorization of a given case into a family based on pattern recognition, and the second step is more meticulous observation, such as identification of different severities of the same pattern or subtle but distinctive findings. Since major skeletal dysplasias are limited in number, radiologists can be familiar with the representative patterns of these disorders. The authors describe a stepwise radiologic approach to diagnosing major skeletal dysplasia families and review the clinical and genetic features of these disorders. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center. and
Topics: Male; Humans; Osteochondrodysplasias; Bone Diseases, Developmental; Radiography; Hand Deformities, Congenital
PubMed: 37053103
DOI: 10.1148/rg.220067 -
Frontiers in Endocrinology 2022Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the...
Skeletal dysplasias comprise a heterogenous group of developmental disorders of skeletal and cartilaginous tissues. Several different forms have been described and the full spectrum of their clinical manifestations and underlying genetic causes are still incompletely understood. We report a three-generation Finnish family with an unusual, autosomal dominant form of osteochondrodysplasia and an empty sella. Affected individuals (age range 24-44 years) exhibit unusual codfish-shaped vertebrae, severe early-onset and debilitating osteoarthritis and an empty sella without endocrine abnormalities. Clinical characteristics also include mild dysmorphic features, reduced sitting height ratio, and obesity. Whole-exome sequencing excluded known skeletal dysplasias and identified a novel heterozygous missense mutation c.899C>T (p.Thr300Met) in , confirmed by Sanger sequencing. TBX2 is important for development of the skeleton and the brain and three prior reports have described variations in in patients portraying a complex phenotype with vertebral anomalies, craniofacial dysmorphism and endocrine dysfunctions. Our mutation lies near a previously reported disease-causing variant and is predicted pathogenic with deleterious effects on protein function. Our findings expand the current spectrum of skeletal dysplasias, support the association of mutations with skeletal dysplasia and suggest a role for TBX2 in development of the spinal and craniofacial structures and the pituitary gland.
Topics: Abnormalities, Multiple; Bone Diseases, Developmental; Humans; Osteochondrodysplasias; Phenotype; Exome Sequencing
PubMed: 35311234
DOI: 10.3389/fendo.2022.845889