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Advances in Experimental Medicine and... 2010Osteochondrodysplasias like thanatophoric dysplasia, osteogenesis imperfecta, achondroplasia, and other genetic skeletal disorders like fibrodysplasia ossificans... (Review)
Review
Osteochondrodysplasias like thanatophoric dysplasia, osteogenesis imperfecta, achondroplasia, and other genetic skeletal disorders like fibrodysplasia ossificans progressiva are infrequently seen in clinical practice. In cases of sporadic achondroplasia as well as in fibrodysplasia ossificans progressiva, there is a strong association with paternal age, a relationship that is less evident in other genetic osteochondral diseases. No other constitutional or environmental factor has proven to be associated with these disorders. The use of prenatal ultrasonography as a routine component of prenatal care is crucial in the early suspicion of osteochondrodysplasias whereas definitive diagnosis is usually obtained by pre-natal molecular analysis. In the case of fibrodysplasia ossificans progressiva, recognition of congenital great toe malformations associated with rapidly-appearing soft tissue swelling is sufficient to make the proper clinical diagnosis, which can be confirmed by genetic testing. Large regional centres will improve diagnosis performance, provide accurate genetic counselling, and ensure an integral assistance for these often severe and incapacitating conditions.
Topics: Female; Humans; Male; Myositis Ossificans; Osteochondrodysplasias; Pregnancy; Prenatal Diagnosis; Rare Diseases
PubMed: 20824454
DOI: 10.1007/978-90-481-9485-8_19 -
Experimental and Molecular Pathology Apr 2017Thanatophoric dysplasia (TD), the most common lethal skeletal dysplasia, is a de novo genetic disease caused by a mutation in the fibroblast growth factor receptor 3...
Thanatophoric dysplasia (TD), the most common lethal skeletal dysplasia, is a de novo genetic disease caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. "Thanatophoric" means "dead bearing" in Greek. Because FGFR3 is the main modulator of bone maturation, typical features of TD include short extremities, curved femur, clover-leaf skull, small narrow chest, and platyspondyly. TD can be classified into two subgroups according to the morphologic findings, with prominent curved femur suggesting type I TD (TD 1) and with marked clover-leaf skull and relatively straight long bones, favoring type II TD (TD 2). However, considering the genetic profiles, TD 1 and TD 2 could be confidently delineated. Here, we report five genotype-phenotype correlated autopsy cases of TD. Five cases had stigmata of TD on antenatal ultrasonography. Terminations were done at gestational age 16 to 28weeks, after family consultation. In autopsy, all fetuses showed short limbs and clover-leaf skull. The microscopic examination of the bones showed disorganized growth plate, consistent with TD. However, some differences existed in gross and microscopic findings between cases. In genetic analyses, three cases revealed missense mutation of Y373C, while the remaining two cases had missense mutation of S371C and S249C each. They were hot spot mutations of TD 1. A correlation between genotype and phenotype was not apparent due to the limited number of the cases. Therefore, a molecular work up to identify the mutation of FGFR3 is indispensable for TD diagnosis in the era of precision medicine for genetic consultation and future targeted therapy.
Topics: Adult; Autopsy; Exons; Female; Fetus; Genotype; Gestational Age; Humans; Mutation, Missense; Phenotype; Receptor, Fibroblast Growth Factor, Type 3; Skull; Thanatophoric Dysplasia
PubMed: 28249712
DOI: 10.1016/j.yexmp.2017.02.019 -
Osteoarthritis and Cartilage Nov 2018FGFR3 chondrodysplasia is caused by a gain-of-function mutation of the FGFR3 gene. The disease causes abnormal growth plate cartilage and lacks effective drug treatment....
OBJECTIVE
FGFR3 chondrodysplasia is caused by a gain-of-function mutation of the FGFR3 gene. The disease causes abnormal growth plate cartilage and lacks effective drug treatment. We sought to establish an in vivo model for the study of FGFR3 chondrodysplasia pathology and drug testing.
DESIGN
We created cartilage from human induced pluripotent stem cells (hiPSCs) and transplanted the cartilage into the subcutaneous spaces of immunodeficient mice. We then created cartilage from the hiPSCs of patients with FGFR3 chondrodysplasia and transplanted them into immunodeficient mice. We treated some mice with a FGFR inhibitor after the transplantation.
RESULTS
Xenografting the hiPSC-derived cartilage reproduced human growth plate cartilage consisting of zones of resting, proliferating, prehypertrophic and hypertrophic chondrocytes and bone in immunodeficient mice. Immunohistochemistry of xenografts using anti-human nuclear antigen antibody indicated that all chondrocytes in growth plate cartilage were human, whereas bone was composed of human and mouse cells. The pathology of small hypertrophic chondrocytes due to up-regulated FGFR3 signaling in FGFR3 skeletal dysplasia was recapitulated in growth plate cartilage formed in the xenografts of patient-specific hiPSC-derived cartilage. The mean diameters of hypertrophic chondrocytes between wild type and thanatophoric dysplasia were significantly different (95% CI: 13.2-26.9; n = 4 mice, one-way analysis of variance (ANOVA)). The pathology was corrected by systemic administration of a FGFR inhibitor to the mice.
CONCLUSION
The patient-specific growth plate cartilage xenograft model for FGFR3 skeletal dysplasia indicated recapitulation of pathology and effectiveness of a FGFR inhibitor for treatment and warrants more study for its usefulness to study disease pathology and drug testing.
Topics: Animals; Cartilage; Cell Cycle; Cell Differentiation; Cell Proliferation; Disease Models, Animal; Growth Plate; Heterografts; Mice; Mutation; Osteochondrodysplasias; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction
PubMed: 30086379
DOI: 10.1016/j.joca.2018.07.015 -
Ultrasound in Obstetrics & Gynecology :... Aug 2009To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal...
OBJECTIVE
To assess the types and numbers of cases, gestational age at specific prenatal diagnosis and diagnostic accuracy of the diagnosis of skeletal dysplasias in a prenatal population from a single tertiary center.
METHODS
This was a retrospective database review of type, prenatal and definitive postnatal diagnoses and gestational age at specific prenatal diagnosis of all cases of skeletal dysplasias from a mixed referral and screening population between 1985 and 2007. Prenatal diagnoses were grouped into 'correct ultrasound diagnosis' (complete concordance with postnatal pediatric or pathological findings) or 'partially correct ultrasound diagnosis' (skeletal dysplasias found postnatally to be a different one from that diagnosed prenatally).
RESULTS
We included 178 fetuses in this study, of which 176 had a prenatal ultrasound diagnosis of 'skeletal dysplasia'. In 160 cases the prenatal diagnosis of a skeletal dysplasia was confirmed; two cases with skeletal dysplasias identified postnatally had not been diagnosed prenatally, giving 162 fetuses with skeletal dysplasias in total. There were 23 different classifiable types of skeletal dysplasia. The specific diagnoses based on prenatal ultrasound examination alone were correct in 110/162 (67.9%) cases and partially correct in 50/162 (30.9%) cases, (160/162 overall, 98.8%). In 16 cases, skeletal dysplasia was diagnosed prenatally, but was not confirmed postnatally (n = 12 false positives) or the case was lost to follow-up (n = 4). The following skeletal dysplasias were recorded: thanatophoric dysplasia (35 diagnosed correctly prenatally of 40 overall), osteogenesis imperfecta (lethal and non-lethal, 31/35), short-rib dysplasias (5/10), chondroectodermal dysplasia Ellis-van Creveld (4/9), achondroplasia (7/9), achondrogenesis (7/8), campomelic dysplasia (6/8), asphyxiating thoracic dysplasia Jeune (3/7), hypochondrogenesis (1/6), diastrophic dysplasia (2/5), chondrodysplasia punctata (2/2), hypophosphatasia (0/2) as well as a further 7/21 cases with rare or unclassifiable skeletal dysplasias.
CONCLUSION
Prenatal diagnosis of skeletal dysplasias can present a considerable diagnostic challenge. However, a meticulous sonographic examination yields high overall detection. In the two most common disorders, thanatophoric dysplasia and osteogenesis imperfecta (25% and 22% of all cases, respectively), typical sonomorphology accounts for the high rates of completely correct prenatal diagnosis (88% and 89%, respectively) at the first diagnostic examination.
Topics: Algorithms; Biometry; Bone Diseases, Developmental; Female; Genetic Counseling; Gestational Age; Humans; Musculoskeletal Abnormalities; Pregnancy; Pregnancy Outcome; Prenatal Diagnosis; Quality Assurance, Health Care; Retrospective Studies; Ultrasonography
PubMed: 19548204
DOI: 10.1002/uog.6359 -
Molecular Syndromology Feb 2018Mutations in the fibroblast growth factor receptor 3 gene () cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TDI/TDII)....
Mutations in the fibroblast growth factor receptor 3 gene () cause achondroplasia (ACH), hypochondroplasia (HCH), and thanatophoric dysplasia types I and II (TDI/TDII). In this study, we performed a genetic study of 123 Brazilian patients with these phenotypes. Mutation hotspots of the gene were PCR amplified and sequenced. All cases had recurrent mutations related to ACH, HCH, TDI or TDII, except for 2 patients. One of them had a classical TDI phenotype but a typical ACH mutation (c.1138G>A) in combination with a novel c.1130T>C mutation predicted as being pathogenic. The presence of the second c.1130T>C mutation likely explained the more severe phenotype. Another atypical patient presented with a compound phenotype that resulted from a combination of ACH and X-linked spondyloepiphyseal dysplasia tarda (OMIM 313400). Next-generation sequencing of this patient's DNA showed double heterozygosity for a typical de novo ACH c.1138G>A mutation and a maternally inherited c.6del mutation. All mutations were confirmed by Sanger sequencing. A pilot study using high-resolution melting (HRM) technique was also performed to confirm several mutations identified through sequencing. We concluded that for recurrent mutations, HRM can be used as a faster, reliable, and less expensive genotyping test than Sanger sequencing.
PubMed: 29593476
DOI: 10.1159/000486697 -
Human Mutation Jan 2012In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor... (Review)
Review
In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer.
Topics: Bone and Bones; Cartilage; Cell Communication; Cell Proliferation; Chondrocytes; Fibroblast Growth Factors; Gene Expression Regulation; Genes, Lethal; Humans; MAP Kinase Signaling System; Mutation; Natriuretic Peptide, C-Type; Osteochondrodysplasias; Phosphatidylinositol 3-Kinases; Receptor, Fibroblast Growth Factor, Type 3; STAT1 Transcription Factor; Signal Transduction; Skin; Skin Neoplasms
PubMed: 22045636
DOI: 10.1002/humu.21636 -
Human Molecular Genetics Mar 2018Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders...
Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.
Topics: Achondroplasia; Animals; Cartilage; Chondrocytes; Cilia; Ciliopathies; Fibroblast Growth Factors; Growth Plate; Humans; Mice; NIH 3T3 Cells; Phenotype; Primary Cell Culture; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction; Thanatophoric Dysplasia
PubMed: 29360984
DOI: 10.1093/hmg/ddy031 -
Case Reports in Obstetrics and... 2016During a routine prenatal exam, a 36-year-old female in her third pregnancy was diagnosed with fetal hydrops at 11 weeks of gestation. The pregnancy was monitored with...
During a routine prenatal exam, a 36-year-old female in her third pregnancy was diagnosed with fetal hydrops at 11 weeks of gestation. The pregnancy was monitored with periodic ultrasounds; however, spontaneous resolution was not observed. Amniotic fluid examination at 16 weeks of gestation showed a normal karyotype; however, macrocephaly, a narrow thorax, and shortening of the long bones were observed on ultrasonography. With the strong suspicion of a fetal skeletal disease, specifically thanatophoric dysplasia (TD), and after extensive genetic counseling, termination of the pregnancy was performed per the parents' wishes with mechanical cervical dilation and gemeprost (PGE1) administration. Following delivery, the fetus was found to have macrocephaly, a narrow bell-shaped thorax, and a protuberant abdomen, as well as curved long bones, H-shaped platyspondyly, and curved clavicles on skeletal radiography. As a result, the fetus was diagnosed with TD type I. This case illustrates that although TD is a rare disease, an accurate prenatal diagnosis can be made with the use of ultrasonography.
PubMed: 27006844
DOI: 10.1155/2016/1821230 -
International Journal of Biological... Jun 2010Fibroblast growth factor receptor 3 (FGFR3), highly conserved in both humans and murine, is one of key tyrosine kinase receptors for FGF. FGFR3 is expressed in different...
Fibroblast growth factor receptor 3 (FGFR3), highly conserved in both humans and murine, is one of key tyrosine kinase receptors for FGF. FGFR3 is expressed in different tissues, including cartilage, brain, kidney, and intestine at different development stages. Conventional knockout of Fgfr3 alleles leads to short life span, and overgrowth of bone. In clinic, human FGFR3 mutations are responsible for three different types of chondrodysplasia syndromes including achondroplasia (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD). For better understanding of the roles of FGFR3 in different tissues at different stages of development and in pathological conditions, we generated Fgfr3 conditional knockout mice in which loxp sites flank exons 9-10 in the Fgfr3 allele. We also demonstrated that Cre-mediated recombination using Col2a1-Cre, a Cre line expressed in chondrocyte during bone development, results in specific deletion of the gene in tissues containing cartilage. This animal model will be useful to study distinct roles of FGFR3 in different tissues at different ages.
Topics: Animals; Electroporation; Genotype; Mice; Mice, Knockout; Mutation; Receptor, Fibroblast Growth Factor, Type 3; Reverse Transcriptase Polymerase Chain Reaction
PubMed: 20582225
DOI: 10.7150/ijbs.6.327 -
Cell Cycle (Georgetown, Tex.) 2014
Topics: Achondroplasia; Animals; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia
PubMed: 25426543
DOI: 10.4161/15384101.2014.989944