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BMJ Case Reports Jul 2018Apert syndrome is a rare congenital disorder characterised by craniosynostosis, midface hypoplasia and syndactyly of hands and feet. Here we present a case of a...
Apert syndrome is a rare congenital disorder characterised by craniosynostosis, midface hypoplasia and syndactyly of hands and feet. Here we present a case of a 44-year-old woman, with a genetic diagnosis of Apert syndrome from birth, who presented with symptomatic left-sided hip osteoarthritis secondary to femoral abnormalities. She proceeded to have a total hip replacement. This case report describes the rare occurrence to identify a possible association between Apert syndrome and hip abnormalities.
Topics: Acrocephalosyndactylia; Adult; Arthroplasty, Replacement, Hip; Female; Femur; Hip Dislocation; Hip Joint; Humans; Osteoarthritis, Hip
PubMed: 29973408
DOI: 10.1136/bcr-2017-221789 -
Journal of Cellular Physiology Apr 2022The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway plays important roles in the development and growth of the skeleton. Apert syndrome caused by...
The fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway plays important roles in the development and growth of the skeleton. Apert syndrome caused by gain-of-function mutations of FGFR2 results in aberrant phenotypes of the skull, midface, and limbs. Although short limbs are representative features in patients with Apert syndrome, the causative mechanism for this limb defect has not been elucidated. Here we quantitatively confirmed decreases in the bone length, bone mineral density, and bone thickness in the Apert syndrome model of gene knock-in Fgfr2 (EIIA-Fgfr2 ) mice. Interestingly, despite these bone defects, histological analysis showed that the endochondral ossification process in the mutant mice was similar to that in wild-type mice. Tartrate-resistant acid phosphatase staining revealed that trabecular bone loss in mutant mice was associated with excessive osteoclast activity despite accelerated osteogenic differentiation. We investigated the osteoblast-osteoclast interaction and found that the increase in osteoclast activity was due to an increase in the Rankl level of osteoblasts in mutant mice and not enhanced osteoclastogenesis driven by the activation of FGFR2 signaling in bone marrow-derived macrophages. Consistently, Col1a1-Fgfr2 mice, which had osteoblast-specific expression of Fgfr2 S252W, showed significant bone loss with a reduction of the bone length and excessive activity of osteoclasts was observed in the mutant mice. Taken together, the present study demonstrates that the imbalance in osteoblast and osteoclast coupling by abnormally increased Rankl expression in Fgfr2 mutant osteoblasts is a major causative mechanism for bone loss and short long bones in Fgfr2 mice.
Topics: Acrocephalosyndactylia; Animals; Cell Differentiation; Gene Knock-In Techniques; Humans; Mice; Osteoblasts; Osteoclasts; Osteogenesis; RANK Ligand; Receptor, Fibroblast Growth Factor, Type 2; Skull
PubMed: 35048384
DOI: 10.1002/jcp.30682 -
The Application of Clinical Genetics 2020Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately...
BACKGROUND
Pfeiffer syndrome (PS) is an autosomal dominant disorder caused by mutations in fibroblast growth factor receptor FGFR1 and FGFR2 genes, occurring in approximately 1:100,000 live births. PS has a wide range of clinical expression and severity, so early prenatal diagnosis is difficult and genetic counseling is desirable. We describe a PS newborn with her ultrasound and molecular studies.
CASE REPORT
We describe a female term newborn with cloverleaf-shaped skull, facial hypoplasia, low ears, exophthalmos and wide, broad and deviated thumbs and hallux. The patient was diagnosed by ultrasound at 29 WGA and referred to a tertiary care hospital for her follow-up. Molecular test revealed a heterozygous pathogenic variant in intron 8 of the FGFR2 gene (FGFR2: c.940-1G>C). It was a de-novo mutation. At 17 days of life, craniosynostosis correction and a Lefort-III frontomaxillary advancement were performed.
CONCLUSION
Pfeiffer syndrome is a devastating genetic disorder. Prenatal diagnosis according PS morphological features in prenatal ultrasound allows timely genetic counseling, early referral to third-level centers, and close follow-up in the prenatal and postnatal stages.
PubMed: 32848441
DOI: 10.2147/TACG.S251581 -
Cells, Tissues, Organs 2016The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have...
The Apert syndrome is a rare congenital disorder most often arising from S252W or P253R mutations in fibroblast growth factor receptor (FGFR2). Numerous studies have focused on the regulatory role of Apert FGFR2 signaling in bone formation, whereas its functional role in tooth development is largely unknown. To investigate the role of FGFR signaling in cell proliferation and odontogenic differentiation of human dental cells in vitro, we isolated dental pulp and enamel organ epithelia (EOE) tissues from an Apert patient carrying the S252W FGFR2 mutation. Apert primary pulp and EOE cells were established and shown to exhibit normal morphology and express alkaline phosphatase under differentiation conditions. Similar to control cells, Apert dental pulp and EOE cells expressed all FGFRs, with highest levels of FGFR1 followed by FGFR2 and low levels of FGFR3 and FGFR4. However, Apert cells had increased cell growth compared with control cells. Distinct from previous findings in osteoblast cells, gain-of-function S252W FGFR2 mutation did not upregulate the expression of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFRα), but elevated extracellular signal-regulated kinase (ERK) signaling in cells after EGF stimulation. Unexpectedly, there was little effect of the S252W mutation on odontogenic gene expression in dental pulp and EOE cells. However, after inhibition of total FGFR signaling or ERK signaling, the expression of odontogenic genes was upregulated in both dental cell types, indicating the negative effect of whole FGFR signaling on odontogenic differentiation. This study provides novel insights on FGFR signaling and a common Apert FGFR2 mutation in the regulation of odontogenic differentiation of dental mesenchymal and epithelial cells.
Topics: Acrocephalosyndactylia; Alkaline Phosphatase; Cell Differentiation; Cell Proliferation; Cells, Cultured; Dental Pulp; Enamel Organ; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Male; Odontogenesis; Receptor, Fibroblast Growth Factor, Type 1; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Receptor, Fibroblast Growth Factor, Type 4; Receptor, Platelet-Derived Growth Factor alpha; Signal Transduction; Tooth
PubMed: 26613250
DOI: 10.1159/000441349 -
Pediatric Radiology Sep 2019We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in...
We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.
Topics: Abnormalities, Multiple; Acrocallosal Syndrome; Acrocephalosyndactylia; Brain; Child, Preschool; Female; Humans; Infant; Magnetic Resonance Imaging; Olfactory Bulb; Tomography, X-Ray Computed
PubMed: 31399769
DOI: 10.1007/s00247-019-04480-8 -
Human Mutation Oct 2018Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of...
Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5' UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may represent an under-ascertained cause of monogenic disease.
Topics: 5' Untranslated Regions; Acrocephalosyndactylia; Alleles; Base Sequence; DNA Mutational Analysis; Databases, Genetic; Female; Genetic Association Studies; Genetic Variation; Genotype; Haploinsufficiency; Humans; Male; Mutation; Nuclear Proteins; Nucleotide Motifs; Pedigree; Phenotype; Protein Biosynthesis; Twist-Related Protein 1
PubMed: 30040876
DOI: 10.1002/humu.23598 -
Medicine Oct 2022Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal...
RATIONALE
Fetal skeletal anomalies are one of the most common and potentially pathogenic developmental abnormalities detected by ultrasound screening. Any suspected fetal skeletal dysplasias often require further comprehensive evaluations.
PATIENT CONCERNS
Here 4 families with adverse fetal skeletal system histories were enrolled, including their histories of gestation, childbirth, familial skeletal abnormalities, and pregnancy outcomes. The corresponding diagnosis were done by whole exome sequencing (WES) combined with dynamic examination.
DIAGNOSIS
All of the families were definitively diagnosed through cytogenetics, molecular genetics, ultrasound, combined with multidisciplinary evaluation. Both of the fetuses in case 1 and case 2 were diagnosed with thanatophoric dysplasia type I, while the neonate in case 3 was diagnosed with Apert syndrome and a 3-years-old proband daughter with Crouzon syndrome in case 4.
INTERVENTIONS
We conducted karyotyping, copy number variation sequencing (CNV-seq), combined with WES to evaluate genetic conditions of abnormal fetus, neonate or proband patient. WES was preferred to obtain a relatively definitive diagnosis.
OUTCOMES
In cases 1 and 2, the families decided to choose termination of pregnancy due to fatal dysplasias. The couple in case 3, delivered a female baby diagnosed with Apert syndrome. Fortunately, in case 4, the family, which had a 3-years-old baby with Crouzon syndrome, gave birth to a healthy baby through prenatal diagnosis.
LESSONS SUBSECTIONS
Invasive prenatal diagnosis and dynamic assessments for the management of fetal skeletal dysplasias could contribute to revealing possible causes of fetal skeletal abnormalities and help clinicians conduct further genetic counseling in clinical practice.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Child, Preschool; Exome Sequencing; DNA Copy Number Variations; Acrocephalosyndactylia; Fetus; Prenatal Diagnosis; Osteochondrodysplasias; Musculoskeletal Abnormalities; Craniofacial Dysostosis; Ultrasonography, Prenatal
PubMed: 36316869
DOI: 10.1097/MD.0000000000031321 -
Medicine Sep 2020Apert syndrome (AS) is an autosomal dominant inheritance pattern of the most severe craniosynostosis syndrome. AS is characterized by synostosis of cranial sutures and...
RATIONALE
Apert syndrome (AS) is an autosomal dominant inheritance pattern of the most severe craniosynostosis syndrome. AS is characterized by synostosis of cranial sutures and acrocephaly, including brachycephaly, midfacial hypoplasia, and syndactyly of the hands and feet. Patients with AS often present with craniosynostosis, severe syndactyly, and skin, skeletal, brain, and visceral abnormalities.
PATIENT CONCERNS
A pregnant Chinese woman presented with a fetus at 23 + 5 weeks of gestation with suspected AS in a prenatal ultrasound examination. Following ultrasound, the pregnancy underwent spontaneous abortion. Gene sequencing was performed on the back skin of the dead fetus.
DIAGNOSIS
The diagnosis of AS was confirmed on the basis of clinical manifestations of the fetus, and a de novo mutation in the fibroblast growth factor receptor 2 (FGFR2) gene was identified.
INTERVENTIONS
The couple finally chose to terminate the pregnancy based on the ultrasonic malformations and the risk of the parents having a neonate with AS in the future is small. However, any future pregnancy must be assessed by prenatal diagnosis.
OUTCOMES
The dead fetus presented with bilateral skull deformation. Additionally, there were bilateral changes to the temporal bone caused by inwards movement leading to concave morphology, a "clover" sign, and syndactyly from the index finger/second toe to the little finger/little toe. AS was diagnosed by genetic testing, which showed a p.S137W (c.410C>G, chr10:123279677) mutation in the FGFR2 gene.
LESSONS
Clinicians should be aware that there are a variety of ultrasound findings for AS. Therefore, genetic testing should be used when appropriate to confirm diagnosis of AS.
Topics: Abortion, Spontaneous; Acrocephalosyndactylia; Female; Humans; Prenatal Diagnosis; Receptor, Fibroblast Growth Factor, Type 2; Ultrasonography, Prenatal
PubMed: 32991447
DOI: 10.1097/MD.0000000000022340 -
Molecular Genetics & Genomic Medicine Sep 2019Preaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly...
BACKGROUND
Preaxial polydactyly type IV, also referred as polysyndactyly, has been described in a few syndromes. We present three generations of a family with preaxial polydactyly type IV and other clinical features of Greig cephalopolysyndactyly syndrome (GCPS).
METHODS AND RESULTS
Sequencing analysis of the GLI3 coding region identified a novel donor splice site variant NC_000007.14(NM_000168.6):c.473+3A>T in the proband and the same pathogenic variant was subsequently identified in other affected family members. Functional analysis based on Sanger sequencing of the proband's complementary DNA (cDNA) sample revealed that the splice site variant c.473+3A>T disrupts the original donor splice site, thus leading to exon 4 skipping. Based on further in silico analysis, this pathogenic splice site variant consequently results in a truncated protein NP_000159.3:p.(His123Argfs*57), which lacks almost all functionally important domains. Therefore, functional cDNA analysis confirmed that the haploinsufficiency of the GLI3 is the cause of GCPS in the affected family members.
CONCLUSION
Despite the evidence provided, pathogenic variants in the GLI3 do not always definitely correlate with syndromic or nonsyndromic clinical phenotypes associated with this gene. For this reason, further transcriptomic and proteomic evaluation could be suggested.
Topics: Acrocephalosyndactylia; Child; DNA, Complementary; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Mutation; Nerve Tissue Proteins; Pedigree; Phenotype; Proteomics; Sequence Analysis, DNA; Transcriptome; Zinc Finger Protein Gli3
PubMed: 31325247
DOI: 10.1002/mgg3.878 -
Developmental Dynamics : An Official... Mar 2021Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast...
Aberrantly activated Wnt/β-catenin pathway co-receptors LRP5 and LRP6 regulate osteoblast differentiation in the developing coronal sutures of an Apert syndrome (Fgfr2 ) mouse model.
BACKGROUND
Apert syndrome is an autosomal, dominant inherited disorder characterized by craniosynostosis and syndactyly caused by gain-of-function mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. Wnt/β-catenin signaling plays critical roles in regulating the skeletal development. Here, we analyzed the role of this pathway in the developing coronal sutures (CS) of a murine Apert syndrome model (Fgfr2 ).
RESULTS
We observed aberrantly increased mRNA expression of Lrp5 and Lrp6 in CS of Fgfr2 mice, whereas both wild type (WT) and Fgfr2 mice showed similar expression of other Wnt/β-catenin-related genes, such as Wnt3, Wnt3a, Fzd4, Fzd6, Axin2, and Dkk1 as evidenced by in situ hybridization. Significantly increased Lrp5 and Lrp6 mRNA expression was observed by quantitative PCR analysis of cultured cells isolated from CS of Fgfr2 mice. Phospho-LRP5, phospho-LRP6, and non-phospho-β-catenin were upregulated in Fgfr2 CS compared with that in WT CS. Short-interfering RNA targeting Lrp5 and Lrp6 significantly reduced runt-related transcription factor 2, collagen type 1 alpha 1, and osteocalcin mRNA expression, and alkaline phosphatase activity in cultured cells.
CONCLUSIONS
The Wnt/β-catenin pathway was activated in the CS of Fgfr2 mice during craniofacial development, suggesting the involvement of the Wnt/β-catenin pathway in the pathogenesis of CS synostosis in Fgfr2 mice.
Topics: Acrocephalosyndactylia; Amino Acid Substitution; Animals; Cell Differentiation; Cranial Sutures; Disease Models, Animal; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Mice; Mice, Transgenic; Mutation, Missense; Osteoblasts; Receptor, Fibroblast Growth Factor, Type 2; Wnt Signaling Pathway; beta Catenin
PubMed: 32822074
DOI: 10.1002/dvdy.239