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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 -
Taiwanese Journal of Obstetrics &... Jun 2017The aim of the study was to determine whether the biparietal diameter/femur length (BPD/FL) ratio can be used to detect thanatophoric dysplasia in the first trimester of... (Review)
Review
Can biparietal diameter-to-femur length ratio be a useful sonographic marker for screening thanatophoric dysplasia since the first trimester? A literature review of case reports and a retrospective study based on 10,293 routine fetal biometry measurements.
OBJECTIVE
The aim of the study was to determine whether the biparietal diameter/femur length (BPD/FL) ratio can be used to detect thanatophoric dysplasia in the first trimester of pregnancy.
MATERIALS AND METHODS
Twenty-four reported cases of thanatophoric dysplasia diagnosed based on ultrasonographic results with molecular or radiographic diagnosis were included. All sonographic measurement records were extracted and reviewed, and the BPD/FL ratio was calculated for each gestational week. In addition, 10,293 routine fetal biometry measurements from 1395 cases of patients without skeletal dysplasia were compared.
RESULTS
The BPD/FL ratio in the control group decreased to less than 3 prior to gestational week 13, and to less than 2 prior to week 18. Of the 27 BPD/FL ratios obtained from 24 cases of thanatophoric dysplasia, none was in the control range.
CONCLUSION
The BPD/FL ratio may be used to detect lethal skeletal dysplasias such as thanatophoric dysplasia since the first trimester.
Topics: Adult; Biometry; Female; Femur; Fetal Diseases; Gestational Age; Humans; Parietal Bone; Pregnancy; Pregnancy Trimester, First; Retrospective Studies; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 28600053
DOI: 10.1016/j.tjog.2017.04.021 -
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 -
Ultrasound in Obstetrics & Gynecology :... Nov 2014To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral...
OBJECTIVE
To determine the incidence of temporal lobe dysplasia (TLD) detected on prenatal ultrasound in thanatophoric dysplasia (TD) over an 11-year period in a tertiary referral center.
METHODS
An 11-year retrospective review of perinatal autopsies from 2002 to 2013 was performed to identify cases of TD. The ultrasound images and corresponding reports of all TD cases were examined for the presence of TLD. The same set of images subsequently underwent a retrospective review by a perinatal radiologist with knowledge of the features of TLD to determine whether they could be identified.
RESULTS
Thirty-one cases of TD underwent perinatal autopsy, and prenatal ultrasound imaging was available for review in 24 (77%). Mean gestational age at diagnosis of TD was 21.3 (range, 18-36) weeks. TLD was identified and reported in 6/24 (25%) cases; all six cases occurred after 2007. Retrospective interpretation of the ultrasound images identified features of TLD in 10 additional cases. In total, 16/24 (67%) cases displayed sonographic evidence of TLD. Temporal trends showed that TLD features were present in 50% (5/10) of all TD cases between 2002 and 2006 and in 79% (11/14) of those detected between 2007 and 2013.
CONCLUSIONS
At present, the detection rate of TLD by ultrasound is low but may be increased by modified brain images that enhance visualization of the temporal lobes. Prenatal identification of TLD may help in the prenatal diagnosis of TD and thus provide more accurate prenatal counseling and guide molecular investigations to confirm the specific diagnosis of TD.
Topics: Adult; Autopsy; Female; Gestational Age; Humans; Maternal Age; Pregnancy; Pregnancy Outcome; Retrospective Studies; Temporal Lobe; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 24585534
DOI: 10.1002/uog.13337 -
Annals of Medicine and Surgery (2012) Nov 2023Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is...
INTRODUCTION AND IMPORTANCE
Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is characterized by a conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. This disorder can be diagnosed antenatally as early as 13 weeks of gestation.
CASE PRESENTATION
The authors reported a case of thanatophoric dysplasia on USG in a 19 year old young consanguineous female in her second trimester of pregnancy. Ultrasound examination showed a clover leaf-shaped skull, a widened anterior fontanel, a coarse and edematous face, a flattened nasal bridge, a short neck, a low set of ears, shortening of both upper and lower limbs with short fingers, bowed thighs and legs, and a relatively narrow thorax.
CLINICAL DISCUSSION
Lung hypoplasia, polyhydramnios, and hydrops in affected individuals lead to a poor prognosis. Hence, timely intervention should be done to avoid a poor prognosis. However, a mix of sonographic, genetic, histological, and autopsy studies are applied to make the most accurate diagnosis.
CONCLUSION
The authors reported this case due to the rarity of this condition and the need for a systematic and multidisciplinary approach.
PubMed: 37915702
DOI: 10.1097/MS9.0000000000001356 -
Case Reports in Obstetrics and... 2021Obstetric ultrasonography is routinely used to screen for fetal anomalies. Thanatophoric dysplasia (TD) is one of the common though rare lethal skeletal dysplasia,...
INTRODUCTION
Obstetric ultrasonography is routinely used to screen for fetal anomalies. Thanatophoric dysplasia (TD) is one of the common though rare lethal skeletal dysplasia, detected during routine ultrasound scan. TD is caused by a mutation in FGFR3 gene. Characteristic features include shortening of limbs, macrocephaly and platyspondyly. In our local setting, it is common to miss the diagnosis in the early scans due to lack of expertise of the sonographers. To the best of our knowledge, this is the first publication from Ghana. . We present the case of a 33-year-old woman who was referred to the facility on account of ultrasound scan report suggestive of thanatophoric dysplasia type 1 at 34 weeks of a female baby. The diagnosis was not made despite the mother being a regular antenatal attendant, until a fifth scan done at 34 weeks reported features suggestive of thanatophoric dysplasia. The ultrasound scan features included a biparietal diameter of 37weeks, femur length-24weeks, narrowed thoracic cage with hypoplastic lungs and short ribs. The liquor volume was increased with amniotic fluid index (AFI) of 38.4 cm. The femur, tibia, fibula, humerus, ulna, and radius were shortened (micromelia). The diagnosis of thanatophoric dysplasia type 1 was confirmed on autopsy.
CONCLUSION
This report was aimed to highlight the potential contribution of ultrasound scan in the diagnosis of thanatophoric dysplasia in our setting.
PubMed: 33953997
DOI: 10.1155/2021/9940063 -
JNMA; Journal of the Nepal Medical... Mar 2020Thanatophoric skeletal dysplasiais the most lethal, rare, sporadic birth defect due to de novo mutation in the fibroblast growth factor receptor-3. Clinically this is...
Thanatophoric skeletal dysplasiais the most lethal, rare, sporadic birth defect due to de novo mutation in the fibroblast growth factor receptor-3. Clinically this is characterized by shortening of the limbs (micromelia), small conical thorax, flat vertebral bodies and macrocephaly at birth. We encountered a similar case with ultrasonographic findings suggestive of Thanatophoric Skeletal Dysplasia which resulted in the death of the baby within an hour of birth. Almost all cases of this condition have been reported to have died interuterinally or a few days after birth.
Topics: Cesarean Section; Fatal Outcome; Female; Gestational Age; Humans; Infant, Newborn; Male; Pregnancy; Thanatophoric Dysplasia; Young Adult
PubMed: 32347827
DOI: 10.31729/jnma.4488 -
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 -
Taiwanese Journal of Obstetrics &... Feb 2018We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal... (Review)
Review
Prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II and a review of prenatal diagnosis of brain anomalies associated with thanatophoric dysplasia.
OBJECTIVE
We present prenatal diagnosis of hydrancephaly and enlarged cerebellum and cisterna magna in a fetus with thanatophoric dysplasia type II (TD2) and a review of prenatal diagnosis of brain anomalies associated with TD.
CASE REPORT
A 33-year-old woman was referred for genetic counseling at 25 weeks of gestation because of fetal ultrasound abnormalities. Prenatal ultrasound at 14 weeks of gestation revealed an increased nuchal translucency (NT) and hydrocephalus. Level II ultrasound examination at 25 weeks of gestation revealed hydrancephaly, macrocephaly, a cloverleaf skull, frontal bossing, enlarged cerebellum and cisterna magna, a narrow chest, small ribs, short straight limbs. Amniocentesis revealed a karyotype of 46,XX. FGFR3 mutation analysis using the DNA extracted from uncultured amniocytes revealed a genotype of WT/c.1948A>G (p.Lys650Glu). The result was consistent with a K650E mutation in FGFR3 and TD2. The pregnancy was subsequently terminated.
CONCLUSION
Fetuses with TD2 may present increased NT, early onset hydrocephalus, enlarged cerebellum and cisterna magna, and hydrancephaly on prenatal ultrasound.
Topics: Amniocentesis; Cerebellum; Cisterna Magna; DNA Mutational Analysis; Female; Humans; Hydranencephaly; Karyotype; Mutation; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Skull; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 29458880
DOI: 10.1016/j.tjog.2017.12.020 -
Journal of Bone and Mineral Research :... Apr 2018Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses...
Osteogenesis imperfecta (OI) is a strikingly heterogeneous group of disorders with a broad range of phenotypic variations. It is also one of the differential diagnoses in bent bone dysplasias along with campomelic dysplasia and thanatophoric dysplasia and can usually be distinguished by decreased bone mineralization and bone fractures. Bent bone dysplasias also include syndromes such as kyphomelic dysplasia (MIM:211350) and mesomelic dysplasia Kozlowski-Reardon (MIM249710), both of which have been under debate regarding whether or not they are a real entity or simply a phenotypic manifestation of another dysplasia including OI. Bruck syndrome type 2 (BRKS2; MIM:609220) is a rare form of autosomal recessive OI caused by biallelic PLOD2 variants and is associated with congenital joint contractures with pterygia. In this report, we present six patients from four families with novel PLOD2 variants. All cases had multiple fractures. Other features ranged from prenatal lethal severe angulation of the long bones as in kyphomelic dysplasia and mesomelic dysplasia Kozlowski-Reardon through classical Bruck syndrome to moderate OI with normal joints. Two siblings with a kyphomelic dysplasia-like phenotype who were stillborn had compound heterozygous variants in PLOD2 (p.Asp585Val and p.Ser166*). One infant who succumbed at age 4 months had a bent bone phenotype phenotypically like skeletal dysplasia Kozlowski-Reardon (with mesomelic shortening, camptodactyly, retrognathia, cleft palate, skin dimples, but also with fractures). He was homozygous for the nonsense variant (p.Trp561*). Two siblings had various degrees of Bruck syndrome caused by the homozygous missense variant, p.His687Arg. Furthermore a boy with a clinical presentation of moderate OI had a possibly pathogenic homozygous variant p.Trp588Cys. Our experience of six patients with biallelic pathogenic variants in PLOD2 expands the phenotypic spectrum in the PLOD2-related phenotypes. © 2017 American Society for Bone and Mineral Research.
Topics: Abnormalities, Multiple; Adult; Amino Acid Substitution; Arthrogryposis; Bone Diseases, Developmental; Female; Humans; Infant, Newborn; Male; Mutation, Missense; Osteogenesis Imperfecta; Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase
PubMed: 29178448
DOI: 10.1002/jbmr.3348