Disease Pathophysiology Research Report

Target Disease

• Disease Name: Thanatophoric Dysplasia Type 2 (TD2)
• MONDO ID: Not available in the provided context
• Category: Mendelian

Executive Summary

Thanatophoric dysplasia type 2 is a perinatal‑lethal chondrodysplasia caused by a recurrent activating mutation in FGFR3, p.Lys650Glu (K650E), which produces constitutive, ligand‑independent signaling in growth‑plate chondrocytes. This hyperactivation represses chondrocyte proliferation via STAT1/p21 and impedes hypertrophic differentiation through MAPK signaling, collapsing normal endochondral ossification. FGFR3 activation also promotes premature closure of cranial base synchondroses through MAPK‑dependent BMP shifts, contributing to foramen magnum stenosis. Beyond the skeleton, FGFR3 K650E in developing neurons disrupts cortical migration and axon guidance, underlying the temporal/cortical dysplasia reported in TD. Prenatally, a markedly narrow thorax and severe limb shortening foretell respiratory failure and high perinatal lethality. Recent 2023 prenatal genomics studies underscore the high contribution of FGFR3 among fetuses with short long bones and refine severity‑linked diagnostic yield, informing counseling and management. (chen2005rolesoffgf pages 3-4, chen2005rolesoffgf pages 6-7, matsushita2009fgfr3promotessynchondrosis pages 1-2, huang2020enhancedfgfr3activity pages 12-14, huang2023exomesequencingin pages 1-2, huang2023exomesequencingin pages 9-10)

Table: A concise table mapping genes, pathways, cells, anatomical sites, processes, phenotypes, and chemicals implicated in Thanatophoric Dysplasia Type 2, with brief mechanistic notes and supporting evidence IDs for use in knowledge-base curation.

1. Core Pathophysiology

• Causal event and receptor behavior: TD2 is classically caused by FGFR3 p.Lys650Glu (K650E), which “causes all cases of TD‑II” and yields stronger receptor activation than mutations underlying achondroplasia/hypochondroplasia; severity scales with activation level and expression dose. In mouse, the equivalent K644E allele is perinatal‑lethal (die within hours). “TD is the most common lethal neonatal skeletal disorder” with death “presumably as a result of extremely limited respiration caused by impaired thoracic cage development.” (Frontiers in Bioscience, 2005; URL: https://doi.org/10.2741/1671, published May 2005) (chen2005rolesoffgf pages 3-4, chen2005rolesoffgf pages 4-6)
• Downstream pathways in chondrocytes: Activated FGFR3 recruits FRS2α/GRB2/SOS and GAB1 complexes to initiate RAS–RAF–MEK–ERK (MAPK) and PI3K–AKT; PLCγ/IP3/DAG are also engaged. Congenital FGFR3 mutants (including K650E) show elevated basal activity and ligand‑independent signaling at the plasma membrane. (bioRxiv preprint, 2022; URL: https://doi.org/10.1101/2022.04.11.487861, posted Apr 2022) (hartl2022quantitationoffgfr3 pages 1-6)
• Cellular consequences in the growth plate: FGFR3 is a negative regulator of endochondral bone growth; gain‑of‑function reduces chondrocyte proliferation and narrows disorganized proliferative and hypertrophic zones. Mechanistically, FGFR3 activation upregulates STAT1 and cell‑cycle inhibitors (p21 and related CKIs) leading to growth arrest/apoptosis, while ERK/MAPK inhibits hypertrophic differentiation; FGFR3 also downregulates IHH and PTHrP‑R signaling in parallel. (Frontiers in Bioscience, 2005; URL: https://doi.org/10.2741/1671, published May 2005) (chen2005rolesoffgf pages 6-7)
• Synchondrosis closure and cranial base: Chondrocyte‑specific FGFR3‑MAPK activation promotes premature synchondrosis closure and fusion of ossification centers, with MAPK‑dependent increases in Bmp ligand expression and decreases in antagonists, explaining foramen magnum stenosis and early spinal canal narrowing in severe FGFR3 dysplasias. (Human Molecular Genetics, 2009; URL: https://doi.org/10.1093/hmg/ddn339, published Oct 2009) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• Brain malformations: FGFR3 K650E produces constitutive kinase activity; FGFR3 gain‑of‑function in post‑mitotic glutamatergic neurons disrupts RGC mitosis, radial migration, neuronal identity, and axonal tract formation with RNA‑seq showing dysregulated axon guidance (Slit/Robo, Wnt/Frizzled). Neuropathology in FGFR3 GOF human cases includes hippocampal dysplasia, heterotopia, and cortical lamination defects. (Scientific Reports, 2020; URL: https://doi.org/10.1038/s41598-020-75537-0, published Oct 2020) (huang2020enhancedfgfr3activity pages 12-14)

2. Key Molecular Players

• Genes/Proteins (HGNC): FGFR3 (HGNC:3689) is the causal gene; K650E is the canonical TD2 allele, with stronger activation than G380R (achondroplasia) and N540K (hypochondroplasia). Impaired receptor downregulation (e.g., reduced c‑Cbl–mediated ubiquitination) contributes to sustained signaling in some FGFR3 GOF contexts. (Frontiers in Bioscience, 2005; URL: https://doi.org/10.2741/1671, May 2005) (chen2005rolesoffgf pages 4-6)
• Signaling nodes: STAT1 and CDK inhibitors (p21/others) mediate proliferation arrest; RAS–RAF–MEK–ERK suppresses hypertrophic differentiation; PI3K–AKT and PLCγ branches contribute to broader survival and transcriptional programs. (Frontiers in Bioscience, 2005; bioRxiv 2022; URLs above) (chen2005rolesoffgf pages 6-7, hartl2022quantitationoffgfr3 pages 1-6)
• Chemical entities (CHEBI): FGF1 and FGF2 experimental ligands modulate FGFR3; elevated FGFR liganding and overexpression models phenocopy GOF effects on cartilage. (bioRxiv 2022; Frontiers in Bioscience 2005; URLs above) (hartl2022quantitationoffgfr3 pages 1-6, chen2005rolesoffgf pages 6-7)
• Cell types (CL): Growth‑plate chondrocytes (resting/proliferative/pre‑hypertrophic/hypertrophic) are primary effectors; post‑mitotic cortical neurons are affected in brain. (Frontiers in Bioscience 2005; Sci Rep 2020) (chen2005rolesoffgf pages 6-7, huang2020enhancedfgfr3activity pages 12-14)
• Anatomical locations (UBERON): Long bone growth plate; cranial base synchondroses and foramen magnum; ribs/thoracic cage; cerebral cortex. (HMG 2009; Frontiers in Bioscience 2005; Sci Rep 2020) (matsushita2009fgfr3promotessynchondrosis pages 1-2, chen2005rolesoffgf pages 6-7, huang2020enhancedfgfr3activity pages 12-14)

3. Biological Processes (GO terms)

• Negative regulation of chondrocyte proliferation via STAT1/p21 and related CKIs; inhibition of chondrocyte hypertrophic differentiation via MAPK; disruption of endochondral ossification program. (Frontiers in Bioscience 2005) (chen2005rolesoffgf pages 6-7)
• Positive regulation of BMP output in chondrocytes (via MAPK) at synchondroses, accelerating ossification center fusion. (HMG 2009) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• Axon guidance signaling perturbations (Slit/Robo, Wnt/Frizzled) and altered neuronal identity programs in cortex. (Sci Rep 2020) (huang2020enhancedfgfr3activity pages 12-14)
• Receptor tyrosine kinase signaling at the plasma membrane through FRS2/GRB2/SOS and GAB1 scaffolds; PI3K–AKT, PLCγ/IP3–DAG branches. (bioRxiv 2022) (hartl2022quantitationoffgfr3 pages 1-6)

4. Cellular Components

• Plasma membrane: FGFR3 dimerization and trans‑autophosphorylation with docking for FRS2α, GRB2, SHP2, PLCγ; surface signaling may differ from bulk cell extract readouts. (bioRxiv 2022) (hartl2022quantitationoffgfr3 pages 1-6)
• Cytosol: RAS–RAF–MEK–ERK and PI3K–AKT cascades; PLCγ‑mediated second messengers. (bioRxiv 2022) (hartl2022quantitationoffgfr3 pages 1-6)
• Nucleus: STAT1‑dependent transcriptional repression of proliferation via p21 and other CKIs; altered chondrocyte differentiation gene programs. (Frontiers in Bioscience 2005) (chen2005rolesoffgf pages 6-7)

5. Disease Progression (Sequence of Events)

1) De novo FGFR3 K650E occurs in the embryo, encoding a kinase‑domain change that “causes constitutive activation of FGFR3,” stronger than ACH/HCH variants. (Frontiers in Bioscience 2005) (chen2005rolesoffgf pages 3-4) 2) Constitutive RTK signaling engages STAT1/p21‑mediated proliferation arrest and ERK/MAPK‑mediated blockade of hypertrophic differentiation in growth‑plate chondrocytes; growth plate zones narrow and disorganize. (Frontiers in Bioscience 2005) (chen2005rolesoffgf pages 6-7) 3) MAPK‑dependent shift toward BMP ligand expression in synchondroses accelerates cranial base fusion; foramen magnum stenosis/spinal canal narrowing emerge early. (HMG 2009) (matsushita2009fgfr3promotessynchondrosis pages 1-2) 4) Systemically, endochondral ossification fails: long bones are markedly shortened, ribs/thorax remain hypoplastic, cranial vault is large with midface hypoplasia. (Frontiers in Bioscience 2005) (chen2005rolesoffgf pages 3-4) 5) In the brain, FGFR3 GOF disrupts neurogenesis/migration/axon guidance, producing temporal/cortical dysplasia and heterotopia that are characteristic in severe FGFR3 disorders. (Sci Rep 2020) (huang2020enhancedfgfr3activity pages 12-14) 6) Prenatal ultrasound recognizes a narrow thorax and severe limb shortening; perinatal lethality results primarily from respiratory insufficiency due to thoracic hypoplasia. (Frontiers in Bioscience 2005; 2024 ultrasound review) (chen2005rolesoffgf pages 3-4, ward2024skeletaldysplasias pages 1-2)

6. Phenotypic Manifestations (HP terms)

• Severe micromelia and extremely short limbs; narrow thorax leading to respiratory failure; macrocephaly with frontal bossing; foramen magnum stenosis; cortical/temporal lobe dysplasia and heterotopia in some cases. Representative statement: “TD is the most common lethal neonatal skeletal disorder,” with lethality due to impaired thoracic cage development; TD2 is associated with K650E. (Frontiers in Bioscience 2005; 2024 ultrasound review) (chen2005rolesoffgf pages 3-4, ward2024skeletaldysplasias pages 1-2)

7. Recent Developments (2023–2024) and Applications

• Prenatal genomics for fetuses with short long bones:
• In a 2023 trio‑exome cohort (n=94 SLB fetuses), overall diagnostic yield was 40.4%; skeletal dysplasias comprised 37.2% of all cases; FGFR3 accounted for 42.1% of molecular diagnoses. Thanatophoric dysplasia comprised 10.5% of diagnoses. Severity correlated strongly with yield: 72.5% when femur length < −4 SD vs 16.7% for −2 to −4 SD (p<0.001). Authors concluded that ES adds clinically relevant information for counseling and management. (Frontiers in Genetics, 2023; URL: https://doi.org/10.3389/fgene.2023.1032346, published Feb 2023) (huang2023exomesequencingin pages 1-2, huang2023exomesequencingin pages 9-10)
• A 2023 prenatal WES series (n=145) reported an overall trio WES diagnostic rate of 28.1% and the highest yield in musculoskeletal anomalies (51.4%). FGFR3 and COL1A1 were the most common pathogenic genes detected, guiding prognosis and parental decision‑making. (BMC Medical Genomics, 2023; URL: https://doi.org/10.1186/s12920-023-01697-3, published Oct 2023) (qin2023prenatalwholeexomesequencing pages 1-2)
• Ultrasound review (2024) lists TD incidence near 1/20,000 and summarizes TD1 vs TD2 features (TD2 with straight femora and severe craniosynostosis), noting that ultrasound correctly assigns skeletal dysplasia subtypes in ~60–65% of cases antenatally. (Donald School J Ultrasound Obstet Gynecol, 2024; URL: https://doi.org/10.5005/jp-journals-10009-2023, published Jun 2024) (ward2024skeletaldysplasias pages 1-2)
• Mechanistic clarifications and models:
• Quantitative live‑cell readouts (2022) demonstrate ligand‑independent activation for multiple FGFR3 mutants including K650E and map pathway engagement (RAS/MAPK, PI3K/AKT, PLCγ) at the plasma membrane, informing drug‑target engagement strategies. (bioRxiv, 2022; URL above) (hartl2022quantitationoffgfr3 pages 1-6)
• Synchondrosis mechanism (MAPK→BMP) provides a window for timing‑dependent interventions prior to cranial base fusion. (HMG, 2009; URL above) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• Real‑world implementations: Prenatal ES/WES is being integrated after CMA in fetuses with SLB to detect de novo FGFR3 variants, with results materially influencing decisions and perinatal planning; diagnostic rates are highest in severe shortening and multiple anomalies, highlighting selection criteria for testing. (Frontiers in Genetics 2023; BMC Med Genomics 2023) (huang2023exomesequencingin pages 1-2, qin2023prenatalwholeexomesequencing pages 1-2)

8. Expert Opinions and Authoritative Analyses

• Foundational review (Chen & Deng) synthesizes that FGFR3 is a negative regulator of bone growth and that “there is a correlation between the degree of receptor activation and the severity of the dwarfism phenotype,” explicitly associating K650E with TD2 and perinatal lethality due to thoracic hypoplasia. (Frontiers in Bioscience, 2005; URL above) (chen2005rolesoffgf pages 3-4, chen2005rolesoffgf pages 4-6)
• Mechanistic paper (Matsushita et al.) emphasizes that FGFR3–MAPK in chondrocytes drives premature synchondrosis closure via BMP modulation, directly linking pathway biology to foramen magnum stenosis and timing‑sensitive windows for intervention. (HMG, 2009; URL above) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• Neuroscience model (Huang et al.) demonstrates that FGFR3 K650E in neurons is sufficient to produce cortical dysplasia and axonal tract defects, supporting the attribution of TD2 brain malformations to receptor hyperactivation. (Sci Rep, 2020; URL above) (huang2020enhancedfgfr3activity pages 12-14)

9. Relevant Statistics and Data

• TD incidence: approximately 1 in 20,000 births; TD contributes ~29% of lethal skeletal dysplasias in some ultrasound series. (2024 ultrasound review; URL: https://doi.org/10.5005/jp-journals-10009-2023) (ward2024skeletaldysplasias pages 1-2)
• Prenatal ES in SLB fetuses (n=94): 40.4% molecular diagnosis; FGFR3 causes 42.1% of positive diagnoses, with TD ~10.5% of cases; diagnostic yield 72.5% (FL < −4 SD) vs 16.7% (−2 to −4 SD). (Frontiers in Genetics, 2023; URL: https://doi.org/10.3389/fgene.2023.1032346) (huang2023exomesequencingin pages 1-2, huang2023exomesequencingin pages 9-10)
• Prenatal WES (n=145): overall trio yield 28.1%; musculoskeletal anomalies 51.4% yield; FGFR3 among top causal genes. (BMC Med Genomics, 2023; URL: https://doi.org/10.1186/s12920-023-01697-3) (qin2023prenatalwholeexomesequencing pages 1-2)

10. Structured Annotations for Knowledge Base

• Gene/protein (HGNC): FGFR3 (HGNC:3689). Evidence: GOF K650E causes TD2; activation severity correlates with phenotype. (Frontiers in Bioscience 2005; URL above) (chen2005rolesoffgf pages 3-4, chen2005rolesoffgf pages 4-6)
• Biological processes (GO): negative regulation of chondrocyte proliferation via STAT1/p21; MAPK cascade; endochondral ossification; axon guidance in cortex. (Frontiers in Bioscience 2005; HMG 2009; Sci Rep 2020) (chen2005rolesoffgf pages 6-7, matsushita2009fgfr3promotessynchondrosis pages 1-2, huang2020enhancedfgfr3activity pages 12-14)
• Cellular components: plasma membrane FGFR3 complex (FRS2/GRB2/SOS, GAB1), cytosolic ERK and AKT cascades, nuclear STAT1 transcription. (bioRxiv 2022; Frontiers in Bioscience 2005) (hartl2022quantitationoffgfr3 pages 1-6, chen2005rolesoffgf pages 6-7)
• Phenotypes (HP): HP:0000774 Narrow thorax; HP:0005931 Foramen magnum stenosis; HP:0007340 Cortical/temporal lobe dysplasia; HP:0001355 Megalencephaly. (Frontiers in Bioscience 2005; HMG 2009; Sci Rep 2020) (chen2005rolesoffgf pages 3-4, matsushita2009fgfr3promotessynchondrosis pages 1-2, huang2020enhancedfgfr3activity pages 12-14)
• Cell types (CL): CL:0000138 growth‑plate chondrocyte; CL:0000135 hypertrophic chondrocyte; CL:0002603 cortical neuron. (Frontiers in Bioscience 2005; Sci Rep 2020) (chen2005rolesoffgf pages 6-7, huang2020enhancedfgfr3activity pages 12-14)
• Anatomical (UBERON): UBERON:0003860 growth plate; UBERON:0006646 cranial base synchondrosis; UBERON:0010145 foramen magnum; UBERON:0002223 rib/thoracic cage; UBERON:0000956 cerebral cortex. (HMG 2009; Frontiers in Bioscience 2005; Sci Rep 2020) (matsushita2009fgfr3promotessynchondrosis pages 1-2, chen2005rolesoffgf pages 6-7, huang2020enhancedfgfr3activity pages 12-14)
• Chemicals (CHEBI): CHEBI:30627 FGF1; CHEBI:31672 FGF2. (bioRxiv 2022; Frontiers in Bioscience 2005) (hartl2022quantitationoffgfr3 pages 1-6, chen2005rolesoffgf pages 6-7)

11. Direct Quotes Supporting Key Statements

• “K650E mutation causes all cases of TD‑II.” and “TD is the most common lethal neonatal skeletal disorder… [lethality] as a result of extremely limited respiration caused by impaired thoracic cage development.” (Frontiers in Bioscience, 2005; URL: https://doi.org/10.2741/1671) (chen2005rolesoffgf pages 3-4)
• “Among these [FGFR3 substitutions], the degree of receptor activation correlates with the severity of dwarfism… mice carrying K644E (equivalent to human K650E) show most severe phenotypes, and die within few hours after birth.” (Frontiers in Bioscience, 2005; URL above) (chen2005rolesoffgf pages 4-6)
• “FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway,” with increased Bmp ligands and decreased antagonists in chondrocytes. (Human Molecular Genetics, 2009; URL: https://doi.org/10.1093/hmg/ddn339) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• “Gain‑of‑function in FGFR3… causes constitutive activation of FGFR3 tyrosine kinase,” and mouse neuronal GOF disrupts radial migration and axonal tracts; RNA‑seq shows altered axon guidance. (Scientific Reports, 2020; URL: https://doi.org/10.1038/s41598-020-75537-0) (huang2020enhancedfgfr3activity pages 12-14)

12. Clinical and Translational Implications

• Diagnosis: In fetuses with short long bones, trio‑exome sequencing after normal karyotype/CMA yields high diagnostic rates, especially with severe shortening (FL < −4 SD). FGFR3 variants (including TD) are frequent and should be prioritized in targeted panels; ultrasound recognition remains essential but is imperfect for precise subtyping. (Frontiers in Genetics 2023; BMC Med Genomics 2023; 2024 ultrasound review) (huang2023exomesequencingin pages 1-2, qin2023prenatalwholeexomesequencing pages 1-2, ward2024skeletaldysplasias pages 1-2)
• Management: Recognizing TD2’s respiratory lethality is critical for perinatal planning. Premature cranial base fusion suggests early surveillance for foramen magnum stenosis in survivors/variant phenotypes. Timing of any hypothetical growth‑promoting or FGFR3‑modulating interventions would need to precede synchondrosis closure. (HMG 2009) (matsushita2009fgfr3promotessynchondrosis pages 1-2)
• Therapeutic research landscape: While disease‑modifying agents are established for achondroplasia, the mechanistic insights relevant to FGFR3 signaling branches (STAT1/p21; MAPK; PI3K/AKT; PLCγ) and plasma‑membrane activation state reinforce targets for future pathway modulation in FGFR3 chondrodysplasias; however, TD2’s lethality and early onset impose substantial translational barriers. (bioRxiv 2022; Frontiers in Bioscience 2005) (hartl2022quantitationoffgfr3 pages 1-6, chen2005rolesoffgf pages 6-7)

References (URLs and dates embedded above).

References

1. (chen2005rolesoffgf pages 3-4): Lin Chen and C. Deng. Roles of fgf signaling in skeletal development and human genetic diseases. Frontiers in bioscience : a journal and virtual library, 10:1961-76, May 2005. URL: https://doi.org/10.2741/1671, doi:10.2741/1671. This article has 130 citations.

2. (chen2005rolesoffgf pages 6-7): Lin Chen and C. Deng. Roles of fgf signaling in skeletal development and human genetic diseases. Frontiers in bioscience : a journal and virtual library, 10:1961-76, May 2005. URL: https://doi.org/10.2741/1671, doi:10.2741/1671. This article has 130 citations.

3. (matsushita2009fgfr3promotessynchondrosis pages 1-2): T. Matsushita, W. R. Wilcox, Y. Y. Chan, A. Kawanami, H. Bukulmez, G. Balmes, P. Krejci, P. B. Mekikian, K. Otani, I. Yamaura, M. L. Warman, D. Givol, and S. Murakami. Fgfr3 promotes synchondrosis closure and fusion of ossification centers through the mapk pathway. Human Molecular Genetics, 18:227-240, Oct 2009. URL: https://doi.org/10.1093/hmg/ddn339, doi:10.1093/hmg/ddn339. This article has 165 citations and is from a domain leading peer-reviewed journal.

4. (huang2020enhancedfgfr3activity pages 12-14): Jui-Yen Huang, Bruna Baumgarten Krebs, Marisha Lynn Miskus, May Lin Russell, Eamonn Patrick Duffy, Jason Michael Graf, and Hui-Chen Lu. Enhanced fgfr3 activity in postmitotic principal neurons during brain development results in cortical dysplasia and axonal tract abnormality. Scientific Reports, Oct 2020. URL: https://doi.org/10.1038/s41598-020-75537-0, doi:10.1038/s41598-020-75537-0. This article has 15 citations and is from a peer-reviewed journal.

5. (huang2023exomesequencingin pages 1-2): Yanlin Huang, Chang Liu, Hongke Ding, Yu-nan Wang, Lihua Yu, Fang-Fang Guo, Fake Li, Xiaomei Shi, Yan Zhang, and A-Q. Yin. Exome sequencing in fetuses with short long bones detected by ultrasonography: a retrospective cohort study. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1032346, doi:10.3389/fgene.2023.1032346. This article has 21 citations and is from a peer-reviewed journal.

6. (huang2023exomesequencingin pages 9-10): Yanlin Huang, Chang Liu, Hongke Ding, Yu-nan Wang, Lihua Yu, Fang-Fang Guo, Fake Li, Xiaomei Shi, Yan Zhang, and A-Q. Yin. Exome sequencing in fetuses with short long bones detected by ultrasonography: a retrospective cohort study. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1032346, doi:10.3389/fgene.2023.1032346. This article has 21 citations and is from a peer-reviewed journal.

7. (chen2005rolesoffgf pages 4-6): Lin Chen and C. Deng. Roles of fgf signaling in skeletal development and human genetic diseases. Frontiers in bioscience : a journal and virtual library, 10:1961-76, May 2005. URL: https://doi.org/10.2741/1671, doi:10.2741/1671. This article has 130 citations.

8. (hartl2022quantitationoffgfr3 pages 1-6): Ingrid Hartl, Veronika Brumovska, Yasmin Striedner, Atena Yasari, Gerhard J. Schütz, Eva Sevcsik, and Irene Tiemann-Boege. Quantitation of fgfr3 signaling via grb2 recruitment on micropatterned surfaces. bioRxiv, Apr 2022. URL: https://doi.org/10.1101/2022.04.11.487861, doi:10.1101/2022.04.11.487861. This article has 2 citations and is from a poor quality or predatory journal.

9. (ward2024skeletaldysplasias pages 1-2): Kenneth Ward and Pamela Grant. Skeletal dysplasias. Donald School Journal of Ultrasound in Obstetrics and Gynecology, 18:171-175, Jun 2024. URL: https://doi.org/10.5005/jp-journals-10009-2023, doi:10.5005/jp-journals-10009-2023. This article has 0 citations and is from a poor quality or predatory journal.

10. (qin2023prenatalwholeexomesequencing pages 1-2): Yayun Qin, Yanyi Yao, Nian Liu, Bo Wang, Lijun Liu, Hui Li, Tangxinzi Gao, Runhong Xu, Xiaoyan Wang, Fanglian Zhang, and Jieping Song. Prenatal whole-exome sequencing for fetal structural anomalies: a retrospective analysis of 145 chinese cases. BMC Medical Genomics, Oct 2023. URL: https://doi.org/10.1186/s12920-023-01697-3, doi:10.1186/s12920-023-01697-3. This article has 24 citations and is from a peer-reviewed journal.