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Developmental Dynamics : An Official... Apr 2017Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related... (Review)
Review
Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291-309, 2017. © 2016 Wiley Periodicals, Inc.
Topics: Achondroplasia; Animals; Chondrocytes; Growth Plate; Humans; Receptor, Fibroblast Growth Factor, Type 3; Signal Transduction
PubMed: 27987249
DOI: 10.1002/dvdy.24479 -
Advances in Clinical and Experimental... Jun 2021Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias... (Review)
Review
Skeletal dysplasias are a heterogeneous group of congenital bone and cartilage disorders with a genetic etiology. The current classification of skeletal dysplasias distinguishes 461 diseases in 42 groups. The incidence of all skeletal dysplasias is more than 1 in every 5000 newborns. The type of dysplasia and associated abnormalities affect the lethality, survival and long-term prognosis of skeletal dysplasias. It is crucial to distinguish skeletal dysplasias and correctly diagnose the disease to establish the prognosis and achieve better management. It is possible to use prenatal ultrasonography to observe predictors of lethality, such as a bell-shaped thorax, short ribs, severe femoral shortening, and decreased lung volume. Individual lethal or life-limiting dysplasias may have more or less specific features on prenatal ultrasound. The prenatal features of the most common skeletal dysplasias, such as thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, and campomelic dysplasia, are discussed in this article. Less frequent dysplasias, such as asphyxiating thoracic dystrophy, fibrochondrogenesis, atelosteogenesis, and homozygous achondroplasia, are also discussed.
Topics: Female; Humans; Infant, Newborn; Osteochondrodysplasias; Osteogenesis Imperfecta; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 34019743
DOI: 10.17219/acem/134166 -
American Journal of Obstetrics and... Apr 2023This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
This study aimed to determine the incremental yield of prenatal exome sequencing over chromosomal microarray or G-banding karyotype in fetuses with: (1) intrauterine growth restriction related to placental insufficiency or (2) short long bones, in isolated and nonisolated instances for both scenarios.
DATA SOURCES
Data were collected via electronic searches for relevant citations from January 2010 to April 10, 2022 in MEDLINE, Embase, Web of Science, and Cochrane, and using relevant bibliographies and data generated in-house.
STUDY ELIGIBILITY CRITERIA
Included were prospective or retrospective cohort studies and/or case series with: (1) n>5 cases of short long bones and/or intrauterine growth restriction undergoing prenatal sequencing with a clearly defined phenotype including assessment of placental function; (2) testing based on prenatal phenotype only; (3) a nondiagnostic chromosomal microarray/karyotype; and (4) known results of genetic testing.
METHODS
Incremental yield was calculated for each study and as a pooled value for the aforementioned groups using a random-effects model. Results were displayed in forest plots with 95% confidence intervals. Heterogeneity was assessed statistically using Higgins' I. Publication bias was assessed graphically using funnel plots. Quality assessment was performed using modified Standards for Reporting of Diagnostic Accuracy criteria (International Prospective Register of Systematic Reviews registration number CRD42022324680).
RESULTS
Nineteen studies were included (n=452 cases). The apparent incremental yields with prenatal sequencing were: (1) 4% (95% confidence interval, -5.0 to 12; I=0%) in isolated intrauterine growth restriction with evidence of placental insufficiency, (2) 30% (95% confidence interval, 13-47; I=1%) in intrauterine growth restriction with additional structural anomalies, (3) 48% (95% confidence interval, 26-70; I=73%) in isolated short long bones, and (4) 68% (95% confidence interval, 58-77; I=51%) in short long bones with additional skeletal anomalies. Of the 37 short long bone cases with a diagnosis, 32 had a skeletal dysplasia, with thanatophoric dysplasia and osteogenesis imperfecta being the most common (both 21.6% [n=8/37]). In fetuses with short long bones and additional skeletal features, osteogenesis imperfecta was the most common diagnosis (28% [n=57/204]). Where documented, the inheritance patterns were de novo in 75.4% (n=150) of cases.
CONCLUSION
Prenatal sequencing adds substantially to incremental yield over chromosomal microarray in fetuses with short long bones or multisystem intrauterine growth restriction. Robust studies are required to assess the utility of fetal sequencing in isolated intrauterine growth restriction with evidence of placental insufficiency, which cannot be recommended on the basis of current evidence.
Topics: Humans; Pregnancy; Female; Fetal Growth Retardation; Placental Insufficiency; Exome Sequencing; Retrospective Studies; Osteogenesis Imperfecta; Placenta; Prenatal Diagnosis; Ultrasonography, Prenatal
PubMed: 36209938
DOI: 10.1016/j.ajog.2022.09.045 -
Prenatal Diagnosis May 2013To improve the prenatal diagnosis of thanatophoric dysplasia by defining the change in fetal size across gestation and the frequency of sonographic features, and...
OBJECTIVE
To improve the prenatal diagnosis of thanatophoric dysplasia by defining the change in fetal size across gestation and the frequency of sonographic features, and developing non-invasive molecular genetic diagnosis based on cell-free fetal DNA (cffDNA) in maternal plasma.
METHODS
Fetuses with a confirmed diagnosis of thanatophoric dysplasia were ascertained, records reviewed, sonographic features and measurements determined. Charts of fetal size were then constructed using the LMS (lambda-mu-sigma) method and compared with charts used in normal pregnancies and those complicated by achondroplasia. Cases in this cohort referred to our Regional Genetics Laboratory for molecular diagnosis using cffDNA were identified and results reviewed.
RESULTS
Forty-two cases were scanned in our units. Commonly reported sonographic features were very short and sometimes bowed femora, frontal bossing, cloverleaf skull, short fingers, a small chest and polyhydramnios. Limb shortening was obvious from as early as 13 weeks' gestation, with minimal growth after 20 weeks. Analysis of cffDNA in three of these pregnancies confirmed the presence of the c.742C>CT (p.Arg248Cys) or the c.1948A>AG (p.Lys650Glu) mutation in the fibroblast growth factor receptor 3 gene.
CONCLUSION
These data should improve the accuracy of the sonographic diagnosis of thanatophoric dysplasia and have implications for reliable and safe targeted molecular confirmation using cffDNA.
Topics: Adult; DNA; DNA Mutational Analysis; Female; Femur; Fetus; Gestational Age; Growth Charts; Humans; Pregnancy; Prenatal Diagnosis; Receptor, Fibroblast Growth Factor, Type 3; Retrospective Studies; Sensitivity and Specificity; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 23408600
DOI: 10.1002/pd.4066 -
Diagnostics (Basel, Switzerland) Sep 2023This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe...
This paper presents a rare case of fetal hydrops detected at just 23 weeks of gestation in a 22-year-old woman's first pregnancy. The fetal ultrasound revealed severe skeletal anomalies, craniofacial deformities, and thoracic abnormalities, suggesting a complex and severe skeletal dysplasia, potentially type IA Achondrogenesis-a lethal autosomal recessive condition marked by ossification delay. This case highlights the significance of advanced genetic testing, such as next-generation sequencing (NGS) and whole-genome sequencing (WGS), in diagnosing and understanding skeletal dysplasias. Skeletal dysplasias represent a group of genetic disorders that affect osteogenesis. The prevalence of this condition is 1 in 4000 births. Sadly, 25% of affected infants are stillborn, and around 30% do not survive the neonatal period. There is a wide range of rare skeletal dysplasias, each with its own specific recurrence risk, dysmorphic expression, and implications for neonatal survival and quality of life. When skeletal dysplasia is incidentally discovered during routine ultrasound screening in a pregnancy not known to be at risk of a specific syndrome, a systematic examination of the limbs, head, thorax, and spine is necessary to reach the correct diagnosis. Prenatal diagnosis of skeletal dysplasia is crucial for providing accurate counselling to future parents and facilitating the proper management of affected pregnancies. An accurate diagnosis can be a real challenge due to the wide spectrum of clinical presentations of skeletal dysplasia but advances in imaging technologies and molecular genetics have improved accuracy. Additionally, some of these skeletal dysplasias may present clinical overlap, making it especially difficult to distinguish. After the 11th revision of genetic skeletal disorder nosology, there are 771 entities associated with 552 gene mutations. The most common types of skeletal dysplasia are thanatophoric dysplasia, osteogenesis imperfect, achondroplasia, achondrogenesis, and asphyxiating thoracic dystrophy.
PubMed: 37761271
DOI: 10.3390/diagnostics13182905 -
Pediatrics International : Official... Jan 2022This study aimed to analyze the physical and psychosocial development of long-term survivors (age >1 year) of thanatophoric dysplasia (TD).
BACKGROUND
This study aimed to analyze the physical and psychosocial development of long-term survivors (age >1 year) of thanatophoric dysplasia (TD).
METHODS
The participants were 20 long-term survivors recruited from a cohort obtained through a nationwide survey for TD conducted across 147 pediatric departments in Japan between 2012 and 2016. Their guardians consented to participate in this study. Medical and psychosocial information was collected through questionnaires and interviews with primary physicians and guardians.
RESULTS
The participants were 1.2-27.8 years old, and all showed marked growth deficiency. The mean length at birth was 36 cm (-3.4 SD to -7.9 SD). The adult height (age >16 years) was <-15.2 SD. All individuals showed severely delayed psychomotor development. The highest level of psychosocial development was equivalent to that at 2 years of age. Skin disorders (acanthosis nigricans and seborrheic keratoses) were common. Eleven subjects had been hospitalized or institutionalized consistently after birth, and nine had been moved to home care, and four were exclusively orally fed. All individuals required assisted ventilation.
CONCLUSIONS
Long-term survival of TD individuals is common. Some individuals enjoy home-based lives; however, they are severely psychosocially and physically disabled and require meticulous respiratory and nutritional support.
Topics: Child; Infant, Newborn; Adult; Humans; Infant; Adolescent; Child, Preschool; Young Adult; Thanatophoric Dysplasia; Receptor, Fibroblast Growth Factor, Type 3; Acanthosis Nigricans; Surveys and Questionnaires
PubMed: 34597445
DOI: 10.1111/ped.15007 -
The Pan African Medical Journal 2020A case of thanatophoric dysplasia with sudden death at term is hereby presented. Thanatophoric dysplasia is an uncommon, lethal skeletal dysplasia which is associated...
A case of thanatophoric dysplasia with sudden death at term is hereby presented. Thanatophoric dysplasia is an uncommon, lethal skeletal dysplasia which is associated with mutation in the extracellular region of fibroblast growth factor receptor 3 (FGFR3). It is an autosommal dominant condition that has sporadic occurrence and early ultrasound scan has not been of great benefit in its detection. Diagnosis is mostly made in the third trimester. The fetal death is usually due to severe respiratory insufficiency from a reduced thoracic capacity and hypoplastic lungs and/or respiratory failure due to brainstem compression. In view of the autosomal dominance of TD, it will be advisable for a woman with previous history to have prenatal screening to relieve parental anxiety and prevent late detection.
Topics: Adult; Female; Humans; Pregnancy; Pregnancy Trimester, Third; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 33520059
DOI: 10.11604/pamj.2020.37.220.21211 -
Ultrasound in Obstetrics & Gynecology :... Jul 2001
Topics: Adult; Fatal Outcome; Female; Humans; Imaging, Three-Dimensional; Infant, Newborn; Pregnancy; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 11489235
DOI: 10.1046/j.1469-0705.2001.00402.x