-
Oman Medical Journal May 2011Thanatophoric dysplasia is the lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limb dwarfism. The child will be having a...
Thanatophoric dysplasia is the lethal skeletal dysplasia characterized by marked underdevelopment of the skeleton and short-limb dwarfism. The child will be having a short neck, narrow thoracic cage and protuberant abdomen. Other anatomical features include a relatively enlarged head with frontal bossing, prominent eyes, hypertelorism and the depressed nasal bridge. The diagnosis is usually made with the ultrasonography in the second trimester. In this study we report a case of this rare entity with emphasis on its anatomical features, abnormalities and clinical profile with relevant review of literature.
PubMed: 22043415
DOI: 10.5001/omj.2011.47 -
Prenatal Diagnosis Jul 2015Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next-generation... (Comparative Study)
Comparative Study
OBJECTIVE
Accurate prenatal diagnosis of genetic conditions can be challenging and usually requires invasive testing. Here, we demonstrate the potential of next-generation sequencing (NGS) for the analysis of cell-free DNA in maternal blood to transform prenatal diagnosis of monogenic disorders.
METHODS
Analysis of cell-free DNA using a PCR and restriction enzyme digest (PCR-RED) was compared with a novel NGS assay in pregnancies at risk of achondroplasia and thanatophoric dysplasia.
RESULTS
PCR-RED was performed in 72 cases and was correct in 88.6%, inconclusive in 7% with one false negative. NGS was performed in 47 cases and was accurate in 96.2% with no inconclusives. Both approaches were used in 27 cases, with NGS giving the correct result in the two cases inconclusive with PCR-RED.
CONCLUSION
NGS provides an accurate, flexible approach to non-invasive prenatal diagnosis of de novo and paternally inherited mutations. It is more sensitive than PCR-RED and is ideal when screening a gene with multiple potential pathogenic mutations. These findings highlight the value of NGS in the development of non-invasive prenatal diagnosis for other monogenic disorders.
Topics: Achondroplasia; Biomarkers; DNA; False Negative Reactions; Female; Genetic Markers; Genetic Testing; High-Throughput Nucleotide Sequencing; Humans; Male; Maternal Serum Screening Tests; Mutation; Polymerase Chain Reaction; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; Retrospective Studies; Sequence Analysis, DNA; Thanatophoric Dysplasia
PubMed: 25728633
DOI: 10.1002/pd.4583 -
Human Molecular Genetics Dec 2012Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia,...
Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Currently, there are no effective treatments for these skeletal dysplasia diseases. In this study, we screened, using FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia.
Topics: Animals; Carrier Proteins; Cell Differentiation; Cell Line; Cell Proliferation; Cell Survival; Cloning, Molecular; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; HEK293 Cells; Humans; MAP Kinase Signaling System; Mice; Mice, Knockout; Peptide Library; Peptides; Phenotype; Real-Time Polymerase Chain Reaction; Receptor, Fibroblast Growth Factor, Type 3; Sequence Analysis, DNA; Signal Transduction; Skull; Thanatophoric Dysplasia
PubMed: 23014564
DOI: 10.1093/hmg/dds390 -
Ultrasound in Obstetrics & Gynecology :... Jul 1996A series of three cases is reported in which the diagnosis of thanatophoric dysplasia was reached at routine mid-trimester scanning in a District General Hospital. All... (Review)
Review
A series of three cases is reported in which the diagnosis of thanatophoric dysplasia was reached at routine mid-trimester scanning in a District General Hospital. All three patients underwent termination of pregnancy with the diagnosis of thanatophoric dysplasia confirmed by postmortem radiographic and histological examinations. A review of the current literature on thanatophoric dysplasia is given, with special emphasis on the differentiation of the main types of thanatophoric dysplasia from other skeletal abnormalities.
Topics: Abortion, Induced; Adult; Diagnosis, Differential; Female; Humans; Osteochondrodysplasias; Pregnancy; Pregnancy Trimester, Second; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 8843623
DOI: 10.1046/j.1469-0705.1996.08010062.x -
Scientific Reports Oct 2015One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with...
One of the most prominent features of the cerebral cortex of higher mammals is the presence of gyri. Because malformations of the cortical gyri are associated with severe disability in brain function, the mechanisms underlying malformations of the cortical gyri have been of great interest. Combining gyrencephalic carnivore ferrets and genetic manipulations using in utero electroporation, here we successfully recapitulated the cortical phenotypes of thanatophoric dysplasia (TD) by expressing fibroblast growth factor 8 in the ferret cerebral cortex. Strikingly, in contrast to TD mice, our TD ferret model showed not only megalencephaly but also polymicrogyria. We further uncovered that outer radial glial cells (oRGs) and intermediate progenitor cells (IPs) were markedly increased. Because it has been proposed that increased oRGs and/or IPs resulted in the appearance of cortical gyri during evolution, it seemed possible that increased oRGs and IPs underlie the pathogenesis of polymicrogyria. Our findings should help shed light on the molecular mechanisms underlying the formation and malformation of cortical gyri in higher mammals.
Topics: Animals; Astrocytes; Biomarkers; Cell Proliferation; Cerebral Cortex; Disease Models, Animal; Eye Proteins; Ferrets; Fibroblast Growth Factor 8; Homeodomain Proteins; Malformations of Cortical Development; Mice; Neural Stem Cells; Oligodendroglia; PAX6 Transcription Factor; Paired Box Transcription Factors; Phenotype; Repressor Proteins; T-Box Domain Proteins; Thanatophoric Dysplasia
PubMed: 26482531
DOI: 10.1038/srep15370 -
Biophysical Journal Jan 2015Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise because of...
Thanatophoric dysplasia type I (TDI) is a lethal human skeletal growth disorder with a prevalence of 1 in 20,000 to 1 in 50,000 births. TDI is known to arise because of five different mutations, all involving the substitution of an amino acid with a cysteine in fibroblast growth factor receptor 3 (FGFR3). Cysteine mutations in receptor tyrosine kinases (RTKs) have been previously proposed to induce constitutive dimerization in the absence of ligand, leading to receptor overactivation. However, their effect on RTK dimer stability has never been measured experimentally. In this study, we characterize the effect of three TDI mutations, Arg248Cys, Ser249Cys, and Tyr373Cys, on FGFR3 dimerization in mammalian membranes, in the absence of ligand. We demonstrate that the mutations lead to surprisingly modest dimer stabilization and to structural perturbations of the dimers, challenging the current understanding of the molecular interactions that underlie TDI.
Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Humans; Mutation, Missense; Protein Multimerization; Protein Stability; Receptor, Fibroblast Growth Factor, Type 3; Thanatophoric Dysplasia
PubMed: 25606676
DOI: 10.1016/j.bpj.2014.11.3460 -
Prenatal Diagnosis Mar 2021The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and...
OBJECTIVE
The aim is to develop a novel noninvasive prenatal testing (NIPT) method that simultaneously performs fetal aneuploidy screening and the detection of de novo and paternally derived mutations.
METHODS
A total of 68 pregnancies, including 26 normal pregnancies, 7 cases with fetal aneuploidies, 7 cases with fetal achondroplasia or thanatophoric dysplasia, 18 cases with fetal skeletal abnormalities, and 10 cases with β-thalassemia high risk were recruited. Plasma cell-free DNA was amplified by Targeted And Genome-wide simultaneous sequencing (TAGs-seq) to generate around 99% of total reads covering the whole-genome region and around 1% covering the target genes. The reads on the whole-genome region were analyzed for fetal aneuploidy using a binary hypothesis T-score and the reads on target genes were analyzed for point mutations by calculating the minor allelic frequency of loci on FGFR3 and HBB. TAGs-seq results were compared with conventional NIPT and diagnostic results.
RESULTS
In each sample, TAGs-seq generated 44.7-54 million sequencing reads covering the whole-genome region of 0.1-3× and the target genes of >1000×depth. All cases of fetal aneuploidy and de novo mutations of achondroplasia/thanatophoric dysplasia were identified with high sensitivities and specificities except for one false-negative paternal mutation of β-thalassemia.
CONCLUSIONS
TAGs-seq is a novel NIPT method that combines the fetal aneuploidy screening and the detection of de novo FGFR3 mutations and paternal HBB mutations.
Topics: Adult; Aneuploidy; Female; Fetus; Humans; Noninvasive Prenatal Testing; Paternal Inheritance; Pregnancy; Receptor, Fibroblast Growth Factor, Type 3; beta-Thalassemia
PubMed: 33340121
DOI: 10.1002/pd.5879 -
Ultrasound in Obstetrics & Gynecology :... May 2011To collect normative data and test the feasibility and reproducibility of measurement of the maxilla-nasion-mandible (MNM) angle between 16 and 36 weeks' gestation and...
OBJECTIVES
To collect normative data and test the feasibility and reproducibility of measurement of the maxilla-nasion-mandible (MNM) angle between 16 and 36 weeks' gestation and its diagnostic ability in a group of pathological cases.
METHODS
The MNM angle is defined as the angle between the intersection of the maxilla-nasion and mandible-nasion lines in the exact mid-sagittal plane. After assessing reproducibility, the MNM angle was measured in 3D volumes in 241 fetuses cross-sectionally and in 11 fetuses longitudinally. The MNM angle was then tested in 18 pathological cases with facial malformations or syndromes with specific facial features.
RESULTS
The MNM angle could be measured in 92.3% of normal fetuses. Intra- and interobserver intraclass correlation coefficient (ICC) variability was 0.92 and 0.81, respectively. The difference between paired measurements performed by one or two observers was less than 2.5° and 3.6°, respectively in 95% of the cases. The mean MNM angle was 13.5° and did not change significantly during pregnancy (r = - 0.08, P = 0.25). The MNM angle was above the 95(th) centile in all cases of retrognathia and maxillary alveolar ridge interruption. The MNM angle was below the 5(th) centile in Apert syndrome, thanatophoric dysplasia and in two of the three Down syndrome cases.
CONCLUSIONS
The feasibility and reproducibility of measurement of the MNM angle is good. The MNM angle can be used to evaluate the convexity of the fetal profile by enabling an objective assessment of the anteroposterior relationship of the jaws and it may therefore be of help in the diagnosis of retrognathia, maxillary alveolar ridge interruption and flat profile.
Topics: Congenital Abnormalities; Cross-Sectional Studies; Face; Feasibility Studies; Female; Gestational Age; Humans; Imaging, Three-Dimensional; Mandible; Maxilla; Nose; Observer Variation; Pregnancy; Reproducibility of Results; Ultrasonography, Prenatal
PubMed: 20922777
DOI: 10.1002/uog.7768 -
Taiwanese Journal of Obstetrics &... Feb 2017We present perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type I (TD1) in a fetus.
OBJECTIVE
We present perinatal imaging findings and molecular genetic analysis of thanatophoric dysplasia type I (TD1) in a fetus.
CASE REPORT
A 28-year-old woman was referred for genetic counseling at 22 weeks of gestation because of abnormal prenatal ultrasound findings. Level II ultrasound examination revealed a narrow chest, shortened and curved long limbs, protrusion of the abdomen, and macrocephaly. A tentative diagnosis of TD1 was made. After genetic counseling, the pregnancy was terminated and a malformed fetus was delivered. Postnatal radiography findings were consistent with the diagnosis of TD1, with additional findings of short ribs, platyspondyly, and horizontal acetabular roofs. Molecular genetic analysis using umbilical cord tissue revealed a heterozygous mutation of c.2419T>G (p.Ter807Gly) (X807G) in the fibroblast growth factor receptor 3 gene (FGFR3).
CONCLUSION
A second-trimester fetus with a heterozygous c.2419T>G mutation in FGFR3 may present characteristic ultrasound and X-ray findings of TD1.
Topics: Adult; Female; Humans; Mutation; Pregnancy; Pregnancy Trimester, Second; Receptor, Fibroblast Growth Factor, Type 3; Sequence Analysis, DNA; Thanatophoric Dysplasia; Ultrasonography, Prenatal
PubMed: 28254233
DOI: 10.1016/j.tjog.2016.12.013 -
Case Reports in Endocrinology 2014FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia), benign skin tumors...
FGFR3 mutations cause wide spectrum of disorders ranging from skeletal dysplasias (hypochondroplasia, achondroplasia, and thanatophoric dysplasia), benign skin tumors (epidermal nevi, seborrhaeic keratosis, and acanthosis nigricans), and epithelial malignancies (multiple myeloma and prostate and bladder carcinoma). Hypochondroplasia is the most common type of short-limb dwarfism in children resulting from fibroblast growth factor receptor 3 (FGFR3) mutation. Acanthosis nigricans might be seen in severe skeletal dysplasia, including thanatophoric dysplasia and SADDAN syndrome, without a biochemical evidence of hyperinsulinemia. Insulin insensitivity and acanthosis nigricans are uncommonly seen in hypochondroplasia patients with FGFR3 mutations which may represent a new association. We aim to describe the association of hypochondroplasia, acanthosis nigricans, and insulin resistance in a child harboring FGFR3 mutation. To our knowledge, this is the first case report associating the p.N540 with acanthosis nigricans and the second to describe hyperinsulinemia in hypochondroplasia. This finding demonstrates the possible coexistence of insulin insensitivity and acanthosis nigricans in hypochondroplasia patients.
PubMed: 25505998
DOI: 10.1155/2014/840492