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Molecular Genetics & Genomic Medicine Apr 2022Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome....
OBJECTIVE
Craniosynostosis is the result of the early fusion of cranial sutures. Syndromic craniosynostosis includes but not limited by Crouzon syndrome and Pfeiffer syndrome. Considerable phenotypic overlap exists among these syndromes and mutations in FGFR2 may cause different syndromes. This study aims to investigate the explanation of the phenotypic variability via clinical and genetic evaluation for eight patients in a large pedigree.
METHODS
For each patient, comprehensive physical examination, cranial plain CT scan with three-dimensional CT reconstruction (3D-CT), and eye examinations were conducted. Whole exome sequencing was applied for genetic diagnosis of the proband. Variants were analyzed and interpreted following the ACMG/AMP guidelines. Sanger sequencing was performed to reveal genotypes of all the family members.
RESULTS
A pathogenic variant in the FGFR2 gene, c.833G > T (p.C278F), was identified and proved to be co-segregate with the disease. Some symptoms of head, hearing, vision, mouth, teeth expressed differently by affected individuals. Nonetheless, all the eight patients manifested core symptoms of Crouzon syndrome without abnormality in the limbs, which could exclude diagnosis of Pfeiffer syndrome.
CONCLUSION
We have established clinical and genetic diagnosis of Crouzon syndrome for eight patients in a five-generation Chinese family. Variability of clinical features among these familial patients was slighter than that in previously reported sporadic cases.
Topics: Acrocephalosyndactylia; Biological Variation, Population; Craniofacial Dysostosis; Craniosynostoses; Humans; Receptor, Fibroblast Growth Factor, Type 2; Syndrome
PubMed: 35235708
DOI: 10.1002/mgg3.1901 -
Iranian Journal of Allergy, Asthma, and... Feb 2024Sanjad Sakati Syndrome (SSS) is categorized as a neuroendocrine-related disease due to disorders of the nervous and hormonal systems. Since hormonal changes in these...
Sanjad Sakati Syndrome (SSS) is categorized as a neuroendocrine-related disease due to disorders of the nervous and hormonal systems. Since hormonal changes in these patients may affect the nature and function of the immune system. Thus, in this study, cell count and phagocytotic function of neutrophils were evaluated which may be influenced by changes in the hormonal rate and growth factors. In this study, the neutrophil count value and the oxidative burst were evaluated in six patients diagnosed with SSS and six healthy individuals. There was a significant reduction in the neutrophil count observed in SSS patients compared to healthy controls (37.41±7.93 percent vs. 66.5±6.8 percent). However, there was no significant difference in neutrophil oxidative index between patients with SSS and control subjects (172.33±55.08 vs. 217.00±77.38). We concluded that in patients with SSS, the phagocytic activity of neutrophils was not affected by hormonal changes, while the number of neutrophils and neutrophil-to-lymphocyte ratio (NLR) index were decreased.
Topics: Humans; Neutrophils; Respiratory Burst; Intellectual Disability; Leukocyte Count; Lymphocyte Count; Abnormalities, Multiple; Growth Disorders; Acrocephalosyndactylia; Osteochondrodysplasias; Hypoparathyroidism; Seizures
PubMed: 38485906
DOI: 10.18502/ijaai.v23i1.14959 -
ELife Sep 2018The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic...
The earliest developmental origins of dysmorphologies are poorly understood in many congenital diseases. They often remain elusive because the first signs of genetic misregulation may initiate as subtle changes in gene expression, which are hard to detect and can be obscured later in development by secondary effects. Here, we develop a method to trace back the origins of phenotypic abnormalities by accurately quantifying the 3D spatial distribution of gene expression domains in developing organs. By applying Geometric Morphometrics to 3D gene expression data obtained by Optical Projection Tomography, we determined that our approach is sensitive enough to find regulatory abnormalities that have never been detected previously. We identified subtle but significant differences in the gene expression of a downstream target of a mutation associated with Apert syndrome, demonstrating that these mouse models can further our understanding of limb defects in the human condition. Our method can be applied to different organ systems and models to investigate the etiology of malformations.
Topics: Acrocephalosyndactylia; Animals; Biometry; Disease Models, Animal; Gene Expression Profiling; Gene Expression Regulation, Developmental; Mice, Inbred C57BL; Mutation, Missense; Receptor, Fibroblast Growth Factor, Type 2; Tomography, X-Ray Computed
PubMed: 30234486
DOI: 10.7554/eLife.36405 -
BMJ Case Reports Apr 2021Pfeiffer syndrome is a rare inherited craniofacial disorder. Upper airway obstruction is common among patients with Pfeiffer syndrome due to craniosynostosis. They may...
Pfeiffer syndrome is a rare inherited craniofacial disorder. Upper airway obstruction is common among patients with Pfeiffer syndrome due to craniosynostosis. They may also present with lower respiratory tract obstruction due to a rare congenital airway malformation called tracheal cartilaginous sleeve (TCS). We report the case of a patient with Pfeiffer syndrome who presented with recurrent bronchopneumonia, discovered incidentally to have TCS via direct visualisation during tracheostomy. Relevant literature for this rare clinical condition are reviewed and discussed. Clinicians should be aware of TCS when encountering patients with craniosynostosis who present with recurrent lower respiratory tract infections. Careful and meticulous investigations should be performed to look for TCS, especially in patients with craniosynostosis.
Topics: Acrocephalosyndactylia; Cartilage; Child; Child, Preschool; Craniosynostoses; Humans; Infant; Male; Trachea; Tracheostomy
PubMed: 33811090
DOI: 10.1136/bcr-2020-236888 -
Human Molecular Genetics Nov 2014Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these...
Fibroblast growth factor receptor 2 (FGFR2) promotes osteoprogenitor proliferation and differentiation during bone development, yet how the receptor elicits these distinct cellular responses remains unclear. Analysis of the FGFR2-skeletal disorder bent bone dysplasia syndrome (BBDS) demonstrates that FGFR2, in addition to its canonical signaling activities at the plasma membrane, regulates bone formation from within the nucleolus. Previously, we showed that the unique FGFR2 mutations that cause BBDS reduce receptor levels at the plasma membrane and diminish responsiveness to extracellular FGF2. In this study, we find that these mutations, despite reducing canonical signaling, enhance nucleolar occupancy of FGFR2 at the ribosomal DNA (rDNA) promoter. Nucleolar FGFR2 activates rDNA transcription via interactions with FGF2 and UBF1 by de-repressing RUNX2. An increase in the nucleolar activity of FGFR2 in BBDS elevates levels of ribosomal RNA in the developing bone, consequently promoting osteoprogenitor cell proliferation and decreasing differentiation. Identifying FGFR2 as a transcriptional regulator of rDNA in bone unexpectedly reveals a nucleolar route for FGF signaling that allows for independent regulation of osteoprogenitor cell proliferation and differentiation.
Topics: Acrocephalosyndactylia; Animals; Binding Sites; Cell Differentiation; Cell Line; Cell Nucleus; Core Binding Factor Alpha 1 Subunit; DNA, Ribosomal; Fibroblast Growth Factor 2; Gene Expression Regulation; Humans; MAP Kinase Signaling System; Mice; Mutation; Osteoblasts; Pol1 Transcription Initiation Complex Proteins; Protein Binding; Protein Transport; Receptor, Fibroblast Growth Factor, Type 2; Repetitive Sequences, Nucleic Acid; Transcription, Genetic
PubMed: 24908667
DOI: 10.1093/hmg/ddu282 -
PloS One 2014Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are...
Apert syndrome is an autosomal dominantly inherited disorder caused by missense mutations in fibroblast growth factor receptor 2 (FGFR2). Surgical procedures are frequently required to reduce morphological and functional defects in patients with Apert syndrome; therefore, the development of noninvasive procedures to treat Apert syndrome is critical. Here we aimed to clarify the etiological mechanisms of craniosynostosis in mouse models of Apert syndrome and verify the effects of purified soluble FGFR2 harboring the S252W mutation (sFGFR2IIIcS252W) on calvarial sutures in Apert syndrome mice in vitro. We observed increased expression of Fgf10, Esrp1, and Fgfr2IIIb, which are indispensable for epidermal development, in coronal sutures in Apert syndrome mice. Purified sFGFR2IIIcS252W exhibited binding affinity for fibroblast growth factor (Fgf) 2 but also formed heterodimers with FGFR2IIIc, FGFR2IIIcS252W, and FGFR2IIIbS252W. Administration of sFGFR2IIIcS252W also inhibited Fgf2-dependent proliferation, phosphorylation of intracellular signaling molecules, and mineralization of FGFR2S252W-overexpressing MC3T3-E1 osteoblasts. sFGFR2IIIcS252W complexed with nanogels maintained the patency of coronal sutures, whereas synostosis was observed where the nanogel without sFGFR2S252W was applied. Thus, based on our current data, we suggest that increased Fgf10 and Fgfr2IIIb expression may induce the onset of craniosynostosis in patients with Apert syndrome and that the appropriate delivery of purified sFGFR2IIIcS252W could be effective for treating this disorder.
Topics: Acrocephalosyndactylia; Amino Acid Substitution; Animals; Calcification, Physiologic; Cell Differentiation; Cell Line; Codon; Cranial Sutures; Disease Models, Animal; Drug Delivery Systems; Female; Fibroblast Growth Factor 10; Fibroblast Growth Factor 2; Gene Expression; Male; Mice; Mice, Transgenic; Mutation; Nanogels; Osteoblasts; Phenotype; Polyethylene Glycols; Polyethyleneimine; Protein Binding; RNA-Binding Proteins; Receptor, Fibroblast Growth Factor, Type 2; Recombinant Proteins
PubMed: 25003957
DOI: 10.1371/journal.pone.0101693 -
International Journal of Biological... 2017Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial...
Apert syndrome (AS) is a common genetic syndrome in humans characterized with craniosynostosis. Apert patients and mouse models showed abnormalities in sutures, cranial base and brain, that may all be involved in the pathogenesis of skull malformation of Apert syndrome. To distinguish the differential roles of these components of head in the pathogenesis of the abnormal skull morphology of AS, we generated mouse strains specifically expressing mutant FGFR2 in chondrocytes, osteoblasts, and progenitor cells of central nervous system (CNS) by crossing Fgfr2 mice with Col2a1-Cre, Osteocalcin-Cre (OC-Cre), and Nestin-Cre mice, respectively. We then quantitatively analyzed the skull and brain morphology of these mutant mice by micro-CT and micro-MRI using Euclidean distance matrix analysis (EDMA). Skulls of Col2a1-Fgfr2 mice showed Apert syndrome-like dysmorphology, such as shortened skull dimensions along the rostrocaudal axis, shortened nasal bone, and evidently advanced ossification of cranial base synchondroses. The OC-Fgfr2 mice showed malformation in face at 8-week stage. Nestin-Fgfr2 mice exhibited increased dorsoventral height and rostrocaudal length on the caudal skull and brain at 8 weeks. Our study indicates that the abnormal skull morphology of AS is caused by the combined effects of the maldevelopment in calvarias, cranial base, and brain tissue. These findings further deepen our knowledge about the pathogenesis of the abnormal skull morphology of AS, and provide new clues for the further analyses of skull phenotypes and clinical management of AS.
Topics: Acrocephalosyndactylia; Animals; Brain; Chondrocytes; Disease Models, Animal; Female; Magnetic Resonance Imaging; Male; Mice; Mice, Mutant Strains; Receptor, Fibroblast Growth Factor, Type 2; Skull; Skull Base; X-Ray Microtomography
PubMed: 28123344
DOI: 10.7150/ijbs.16287 -
Diagnostic Pathology Jan 2018A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper...
BACKGROUND
A proper balance between the activator and the repressor form of GLI3, a zinc-finger transcription factor downstream of hedgehog signaling, is essential for proper development of various organs during development. Mutations in different domains of the GLI3 gene underlie several congenital diseases including Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS).
CASE PRESENTATION
Here, we describe the case of an overlapped phenotype of these syndromes with agenesis of the gallbladder and the pancreas, bearing a c.2155 C > T novel likely pathogenic variant of GLI3 gene by missense point mutation causing p.P719S at the proteolytic cleavage site.
CONCLUSIONS
Although agenesis of the gallbladder and the pancreas is uncommon in GLI3 morphopathy, a slight difference in the gradient or the balance between activator and repressor in this case may hinder sophisticated spatial and sequential hedgehog signaling that is essential for proper development of gallbladder and pancreas from endodermal buds.
Topics: Abnormalities, Multiple; Acrocephalosyndactylia; Fetus; Gallbladder; Humans; Male; Mutation, Missense; Nerve Tissue Proteins; Pallister-Hall Syndrome; Pancreas; Phenotype; Point Mutation; Zinc Finger Protein Gli3
PubMed: 29368652
DOI: 10.1186/s13000-017-0682-8 -
American Journal of Medical Genetics.... Dec 2017Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue...
Mutations in GLI3, which encodes a transcription factor of the Hedgehog signaling pathway, cause several developmental anomalies linked to inappropriate tissue patterning. Here, we report a novel missense variant in the fifth zinc finger domain of GLI3 (c.1826G>A; p.(Cys609Tyr)) initially identified in a proband with preaxial polydactyly type IV, developmental delay, sensorineural hearing loss, skeletal, and genitourinary anomalies. Additional family members exhibited various digital anomalies such as preaxial polydactyly, syndactyly, and postaxial polydactyly either in isolation or combined. Functional studies of Cys609Tyr GLI3 in cultured cells showed abnormal GLI3 processing leading to decreased GLI3 repressor production, increased basal transcriptional activity, and submaximal GLI reporter activity with Hedgehog pathway activation, thus demonstrating an intriguing molecular mechanism for this GLI3-related phenotype. Given the complexity of GLI3 post-translational processing and opposing biological functions as a transcriptional activator and repressor, our findings highlight the importance of performing functional studies of presumed GLI3 variants. This family also demonstrates how GLI3 variants are variably expressed.
Topics: Acrocephalosyndactylia; Amino Acid Sequence; Animals; Child, Preschool; Female; Fibroblasts; Fingers; Genes, Reporter; Genotyping Techniques; Humans; Mice; Mutation, Missense; Nerve Tissue Proteins; Pedigree; Phenotype; Polydactyly; Repressor Proteins; Sequence Alignment; Sequence Analysis, DNA; Signal Transduction; Thumb; Toes; Zinc Finger Protein Gli3; Zinc Fingers
PubMed: 28884880
DOI: 10.1002/ajmg.a.38415 -
Genetics and Molecular Research : GMR Mar 2015Apert syndrome (AS) is a frequent acrocephalosyndactyly, with autosomal dominant inheritance. AS has been associated with mutations in fibroblast growth factor receptor...
Apert syndrome (AS) is a frequent acrocephalosyndactyly, with autosomal dominant inheritance. AS has been associated with mutations in fibroblast growth factor receptor 2 (FGFR2), and approximately 99% of cases show 2 of the frequent mutations located in exon IIIa (Ser252Trp or Pro253Arg). The purpose of the present study was to describe the mutations in exon IIIa of FGFR2 in Mexican AS patients and the relationships with clinical features. Exon IIIa of FGFR2 from 6 AS patients was amplified by polymerase chain reaction. Mutations in exon IIIa of the FGFR2 gene were identified by digestion with the restriction endonuclease Bstx1 and polyacrylamide gel electrophoresis. PCR fragments were cloned into the PCR 2.1 vector, and both DNA strands were sequenced using the T7 promoter and M13 universal cloning region oligonucleotides. Sequence alignment was performed using the MEGA software version 5. The patients' major clinical features included craniosynostosis, hypertelorism, proptosis, otitis media, midfacial hypoplasia, rhizomelic shortening, and hyperhidrosis. Mutation S252W was present in 4 patients, while the other 2 patients had P253R. In conclusion, either S252W or P253R mutations were present independently in AS patients; however, the 2 mutations were not found together. None of the clinical features were associated with any of the mutations, suggesting that other mutations may be involved in the development of this syndrome.
Topics: Acrocephalosyndactylia; Adult; Base Sequence; Child; Child, Preschool; DNA; DNA Mutational Analysis; Deoxyribonucleases, Type II Site-Specific; Electrophoresis, Polyacrylamide Gel; Exons; Genetic Predisposition to Disease; Humans; Infant; Mexico; Molecular Sequence Data; Mutation, Missense; Receptor, Fibroblast Growth Factor, Type 2; Sequence Homology, Nucleic Acid
PubMed: 25867380
DOI: 10.4238/2015.March.27.19