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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 -
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 -
Annals of Pediatric Endocrinology &... Jun 2022Skeletal dysplasia is a diverse group of disorders that affect bone development and morphology. Currently, approximately 461 different genetic skeletal disorders have...
Skeletal dysplasia is a diverse group of disorders that affect bone development and morphology. Currently, approximately 461 different genetic skeletal disorders have been identified, with over 430 causative genes. Among these, fibroblast growth factor receptor 3 (FGFR3)-related skeletal dysplasia is a relatively common subgroup of skeletal dysplasia. Pediatric endocrinologists may encounter a suspected case of skeletal dysplasia in their practice, especially when evaluating children with short stature. Early and accurate diagnosis of FGFR3-related skeletal dysplasia is essential for timely management of complications and genetic counseling. This review summarizes 5 representative and distinct entities of skeletal dysplasia caused by pathogenic variants in FGFR3 and discusses emerging therapies for FGFR3-related skeletal dysplasias.
PubMed: 35793999
DOI: 10.6065/apem.2244114.057 -
Journal of Community Genetics Oct 2021The aim of the study was to provide accurate information regarding live-born infant survival after diagnosis of fatal fetal anomaly (FFA) to aid decision-making in...
The aim of the study was to provide accurate information regarding live-born infant survival after diagnosis of fatal fetal anomaly (FFA) to aid decision-making in respect of pregnancy management, and to ascertain the natural history of live-born infants with FFAs via a retrospective analysis of death records (2006-2018), from the National Paediatric Mortality Registry (source Central Statistics Office 2019). Diagnoses and survival times were ascertained from narrative records with further ascertainment and reconciliation of trisomies 13 and 18 cases by review of cytogenetic test records, the National Death Events Register and National Perinatal Epidemiology Centre data. During the study period, termination of pregnancy was not permitted under the Irish Constitution. Patients are live-born babies with fatal fetal anomalies whose deaths were registered in the Republic of Ireland. The main outcome measure was construction of anomaly-specific survival curves, or survival time range and median for those anomalies with rare occurrence. Survival curves for anencephaly, bilateral renal agenesis, thanatophoric dysplasia, trisomy 13, and trisomy 18 show that 90% (n = 95), 93% (n = 60), 100% (n = 14), 37% (n = 92) and 33% (n = 162), respectively, were deceased by 24 h and 98%, 100%, 100%, 73%, and 53%, respectively, by 1 week post-delivery. Survival time range and median were calculated for triploidy (3.5 h-20 days; 10.5 days), whose occurrence was rare. Anhydramnios, craniorachischisis, hydranencephaly and severe hydrocephalus were extremely rare and all deaths were neonatal deaths. Our results provide 13 years of national natural history data of live birth FFA survival. This provides objective information to aid obstetric counselling of couples upon diagnosis of an FFA.
PubMed: 34215991
DOI: 10.1007/s12687-021-00534-3 -
Pediatrics International : Official... Aug 2019Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68-8.3 per 100 000 births, but statistical data on the...
BACKGROUND
Thanatophoric dysplasia (TD) is a rare congenital disease of the skeletal system, with an incidence of 1.68-8.3 per 100 000 births, but statistical data on the estimated number of TD patients across Japan are not available. The aim of this study was therefore to investigate the prevalence and prognosis of TD in Japan.
METHODS
A nationwide primary questionnaire survey was conducted.
RESULTS
A total of 127 obstetric, 186 pediatric, and 115 orthopedic facilities provided responses. Excluding duplications, we identified 73 patients with TD. Of the 73 cases, 15 were abortions, four were stillbirths, 51 were live births, and three had unknown details. Of the 51 live newborns, 27 died ≤7 days after birth, with an early neonatal mortality rate of 56%. Of the 24 newborns who survived the early neonatal period, 16 survived for ≥1 year. All of the 24 newborns received respiratory management and survived during the early neonatal period. Of the 51 live newborns, 25 did not receive respiratory management and died ≤2 days after birth.
CONCLUSIONS
The prevalence of TD in Japan is estimated to be at 1.1 (95%CI: 0.84-1.37) per 100 000 births, but the actual incidence is expected to be higher. To our knowledge, we have confirmed for the first time that newborns with TD may not always die during the early neonatal period but can survive the early neonatal period with appropriate respiratory management. Therefore, the term "thanatophoric dysplasia" does not accurately reflect the nature of the disease.
Topics: Adolescent; Child; Child, Preschool; Female; Health Surveys; Humans; Infant; Infant Mortality; Infant, Newborn; Japan; Male; Prevalence; Prognosis; Retrospective Studies; Thanatophoric Dysplasia; Young Adult
PubMed: 31247124
DOI: 10.1111/ped.13927