BACKGROUND Cleidocranial dysplasia(CCD)is an infrequent clinical condition with an autosomal dominant inheritance pattern.It is characterized by abnormal clavicles,patent sutures and fontanelles,supernumerary teeth,an...BACKGROUND Cleidocranial dysplasia(CCD)is an infrequent clinical condition with an autosomal dominant inheritance pattern.It is characterized by abnormal clavicles,patent sutures and fontanelles,supernumerary teeth,and short stature.Approximately 60%-70%of patients with CCD have mutations in the RUNX family transcription factor 2 gene.However,prenatal diagnosis of CCD is difficult when the family history is unknown.CASE SUMMARY We report a rare case of fetal CCD with an unknown family history,confirmed by prenatal ultrasonography and genetic testing at a gestational age of 16 weeks.The genetic reports indicated that the fetus carried pathogenic mutations in the RUNX family transcription factor 2 gene(c.674G>A).After careful consideration,the pregnant woman and her family decided to continue the pregnancy.CONCLUSION Definitive prenatal diagnosis of CCD should include family history,ultrasound diagnosis,and genetic analysis,especially if family history is unknown.展开更多
Cleidocranial dysplasia(CD) is an autosomal dominant syndrome which is characterized by several skeletal malformations such as non-closed fontanelles, skeletal abnormalities of the maxilla and mandible and absence of ...Cleidocranial dysplasia(CD) is an autosomal dominant syndrome which is characterized by several skeletal malformations such as non-closed fontanelles, skeletal abnormalities of the maxilla and mandible and absence of clavicles. Mid-facial hypoplasia and mandibular prognathism are mostly seen jaw abnormalities in CD. In this study, the combined orthodontic-surgical treatment of a patient with CD with class Ⅲ malocclusion and multiple unerupted primary and deciduous teeth is presented.展开更多
Haploinsufficiency of the runt-related transcription factor 2（Runx2） gene is widely known to be responsible for cleidocranial dysplasia（CCD）. To date, more than 190 mutations in Runx2 gene have been reported to be...Haploinsufficiency of the runt-related transcription factor 2（Runx2） gene is widely known to be responsible for cleidocranial dysplasia（CCD）. To date, more than 190 mutations in Runx2 gene have been reported to be related to CCD. In this study, a novel mutation of Runx2 gene was observed in a female with CCD. Genomic DNA was extracted from peripheral venous blood of the proband and eleven members of her family. Genetic testing on these twelve people identified a novel missense mutation（c.895 T〉C, Y299 H） in exon 5 of the RUNX2 gene in the proband. This mutation results in an amino acid change at codon 895（P.Tyr 299 His.） from a tryptophan codon（TAT） to a histidine codon（CAT）. Our finding may further extend the known mutation spectrum of the RUNX2 gene, and facilitate prenatal genetic diagnosis of CCD in the future.展开更多
Introduction: The present study was aimed at advancing the understanding of the pathogenesis of cleidocranial dysplasia (CCD) by presenting a case study based on history, physical examination, typical radiological fea...Introduction: The present study was aimed at advancing the understanding of the pathogenesis of cleidocranial dysplasia (CCD) by presenting a case study based on history, physical examination, typical radiological features, and molecular analysis and a review of the literature. Methods: This study began with a 23-year-old boy (proband) who was referred to the department of oral and maxillofacial radiology with chief complaint of the upper-left first molar tooth and routine dental examination. While evaluating the panoramic radiograph, the patient had approximately 57 teeth in his both of the jaws. Clinical, radiographical and molecular features of the proband, two siblings and their parents were examined and then, DNA analysis was performed. Results: Overall, we present 3 CCD patients with a mutation in the VWRPY motif. The deletion of c. 1754_1757 delTTTG (NM_001024630.2) is determined and it leads to a frame shift mutation and stop codon, p. V585Gfs56X. Conclusions: The present study emphasized the importance of further clinical and molecular investigation when even a single case of CCD is identified within a family. This is the first study performed in Turkey about a family with a mutation in the VWRPY motif. Genotype-phenotype association studies in individuals with CCD are necessary to provide important insights into molecular mechanisms associated with this disease.展开更多
Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for...Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for DNA binding,and is regulated by multiple mechanisms.During the initial stages of osteogenesis,the expression levels of RUNX2 are primarily elevated and then gradually decrease during the formation of osteoblasts and osteocytes.^(1)Abnormal levels of RUNX2 can severely affect osteoblasts and skeletal structure.RUNX2 mutations are linked to cleidocranial dysplasia(CCD),a rare autosomal dominant skeletal disorder characterized by abnormal skeletal phe-notypes.展开更多
Background： Cleidocranial dysplasia （CCD） is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of ...Background： Cleidocranial dysplasia （CCD） is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of the fontanels, midface hypoplasia, short stature, and delayed eruption of permanent and supernumerary teeth. Previous studies reported a connection between CCD and the haploinsufficiency of runt-related transcription factor 2 （RUNX2）. Here, we report a sporadic Chinese case presenting typical symptoms of CCD. Methods： We made genetic testing on this sporadic Chinese case and identified a novel RUNX2 ffameshift mutation： c.1111 dupT. In situ immunofluorescence microscopy and osteocalcin promoter luciferase assay were performed to compare the functions of the RUNX2 mutation with those of wild-type RUNX2. Results： RUNX2 mutation was observed in the perinuclear region, cytoplasm, and nuclei. In contrast, wild-type RUNX2 was confined in the nuclei, which indicated that the subcellular compartmentalization of RUNX2 mutation was partially perturbed. The transactivation function on osteocalcin promoter of the RUNX2 mutation was obviously abrogated. Conclusions： We identified a sporadic CCD patient carrying a novel insertion/frameshift mutation of RUNX2. This finding expanded our understanding of CCD-related phenotypes.展开更多
The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with ...The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.展开更多
基金Supported by Science and Technology Development Plan Project of Weifang,No.2023YX005。
文摘BACKGROUND Cleidocranial dysplasia(CCD)is an infrequent clinical condition with an autosomal dominant inheritance pattern.It is characterized by abnormal clavicles,patent sutures and fontanelles,supernumerary teeth,and short stature.Approximately 60%-70%of patients with CCD have mutations in the RUNX family transcription factor 2 gene.However,prenatal diagnosis of CCD is difficult when the family history is unknown.CASE SUMMARY We report a rare case of fetal CCD with an unknown family history,confirmed by prenatal ultrasonography and genetic testing at a gestational age of 16 weeks.The genetic reports indicated that the fetus carried pathogenic mutations in the RUNX family transcription factor 2 gene(c.674G>A).After careful consideration,the pregnant woman and her family decided to continue the pregnancy.CONCLUSION Definitive prenatal diagnosis of CCD should include family history,ultrasound diagnosis,and genetic analysis,especially if family history is unknown.
文摘Cleidocranial dysplasia(CD) is an autosomal dominant syndrome which is characterized by several skeletal malformations such as non-closed fontanelles, skeletal abnormalities of the maxilla and mandible and absence of clavicles. Mid-facial hypoplasia and mandibular prognathism are mostly seen jaw abnormalities in CD. In this study, the combined orthodontic-surgical treatment of a patient with CD with class Ⅲ malocclusion and multiple unerupted primary and deciduous teeth is presented.
基金financially supported by Science and Technology Program of Wuhan(No.2014062801011270)
文摘Haploinsufficiency of the runt-related transcription factor 2（Runx2） gene is widely known to be responsible for cleidocranial dysplasia（CCD）. To date, more than 190 mutations in Runx2 gene have been reported to be related to CCD. In this study, a novel mutation of Runx2 gene was observed in a female with CCD. Genomic DNA was extracted from peripheral venous blood of the proband and eleven members of her family. Genetic testing on these twelve people identified a novel missense mutation（c.895 T〉C, Y299 H） in exon 5 of the RUNX2 gene in the proband. This mutation results in an amino acid change at codon 895（P.Tyr 299 His.） from a tryptophan codon（TAT） to a histidine codon（CAT）. Our finding may further extend the known mutation spectrum of the RUNX2 gene, and facilitate prenatal genetic diagnosis of CCD in the future.
文摘Introduction: The present study was aimed at advancing the understanding of the pathogenesis of cleidocranial dysplasia (CCD) by presenting a case study based on history, physical examination, typical radiological features, and molecular analysis and a review of the literature. Methods: This study began with a 23-year-old boy (proband) who was referred to the department of oral and maxillofacial radiology with chief complaint of the upper-left first molar tooth and routine dental examination. While evaluating the panoramic radiograph, the patient had approximately 57 teeth in his both of the jaws. Clinical, radiographical and molecular features of the proband, two siblings and their parents were examined and then, DNA analysis was performed. Results: Overall, we present 3 CCD patients with a mutation in the VWRPY motif. The deletion of c. 1754_1757 delTTTG (NM_001024630.2) is determined and it leads to a frame shift mutation and stop codon, p. V585Gfs56X. Conclusions: The present study emphasized the importance of further clinical and molecular investigation when even a single case of CCD is identified within a family. This is the first study performed in Turkey about a family with a mutation in the VWRPY motif. Genotype-phenotype association studies in individuals with CCD are necessary to provide important insights into molecular mechanisms associated with this disease.
基金supported by Valenti FUR(University of Verona),Dalle Carbonare FUR(University of Verona),and the Department of Excellence 2023/2027,MUR,Italy.J.P.acknowledges funding from FCT-Fundacao para a Ciencia e a Tecnologia(Portugal)and FEDER through grant 2022.01199.PTDC.
文摘Runt-related transcription factor 2(RUNX2),also called core-binding factor subunit alpha-1(CBFA1),is the bone-specific transcription factor considered the master gene in osteogenesis,contains a crucial RUNT domain for DNA binding,and is regulated by multiple mechanisms.During the initial stages of osteogenesis,the expression levels of RUNX2 are primarily elevated and then gradually decrease during the formation of osteoblasts and osteocytes.^(1)Abnormal levels of RUNX2 can severely affect osteoblasts and skeletal structure.RUNX2 mutations are linked to cleidocranial dysplasia(CCD),a rare autosomal dominant skeletal disorder characterized by abnormal skeletal phe-notypes.
基金This work was supported by a grant from the Natural Science Foundation of China （No. 81200762）.
文摘Background： Cleidocranial dysplasia （CCD） is an autosomal dominant disease that affects the skeletal system. Common symptoms of CCD include hypoplasia or aplasia of the clavicles, delayed or even absent closure of the fontanels, midface hypoplasia, short stature, and delayed eruption of permanent and supernumerary teeth. Previous studies reported a connection between CCD and the haploinsufficiency of runt-related transcription factor 2 （RUNX2）. Here, we report a sporadic Chinese case presenting typical symptoms of CCD. Methods： We made genetic testing on this sporadic Chinese case and identified a novel RUNX2 ffameshift mutation： c.1111 dupT. In situ immunofluorescence microscopy and osteocalcin promoter luciferase assay were performed to compare the functions of the RUNX2 mutation with those of wild-type RUNX2. Results： RUNX2 mutation was observed in the perinuclear region, cytoplasm, and nuclei. In contrast, wild-type RUNX2 was confined in the nuclei, which indicated that the subcellular compartmentalization of RUNX2 mutation was partially perturbed. The transactivation function on osteocalcin promoter of the RUNX2 mutation was obviously abrogated. Conclusions： We identified a sporadic CCD patient carrying a novel insertion/frameshift mutation of RUNX2. This finding expanded our understanding of CCD-related phenotypes.
基金National Institutes of Health grant F30DE030675(S.A.H.)National Institutes of Health grant T32DE007057(S.A.H.)+7 种基金University of Michigan Rackham Graduate School Pre-Candidate Research Grant(S.A.H.)University of Michigan Rackham Graduate School Candidate Research Grant(S.A.H.)National Institutes of Health grant R35DE034348(N.O.)National Institutes of Health grant R01DE026666(N.O.)National Institutes of Health grant R01DE030630(N.O.)National Institutes of Health grant R01DE029465(R.T.F.)Department of Defense grant W81XWH2010571(R.T.F.)National Institutes of Health grant P30 AR069620(The Michigan Integrative Musculoskeletal.Health Core Center).
文摘The cranial base synchondroses,comprised of opposite-facing bidirectional chondrocyte layers,drive anteroposterior cranial base growth.In humans,RUNX2 haploinsufficiency causes cleidocranial dysplasia associated with deficient midfacial growth.However,how RUNX2 regulates chondrocytes in the cranial base synchondroses remains unknown.To address this,we inactivated Runx2 in postnatal synchondrosis chondrocytes using a tamoxifen-inducible Fgfr3-creER(Fgfr3-Runx2cKO)mouse model.Fgfr3-Runx2cKO mice displayed skeletal dwarfism and reduced anteroposterior cranial base growth associated with premature synchondrosis ossification due to impaired chondrocyte proliferation,accelerated hypertrophy,apoptosis,and osteoclast-mediated cartilage resorption.Lineage tracing reveals that Runx2-deficient Fgfr3+cells failed to differentiate into osteoblasts.Notably,Runx2-deficient chondrocytes showed an elevated level of FGFR3 and its downstream signaling components,pERK1/2 and SOX9,suggesting that RUNX2 downregulates FGFR3 in the synchondrosis.This study unveils a new role of Runx2 in cranial base chondrocytes,identifying a possible RUNX2-FGFR3-MAPK-SOX9 signaling axis that may control cranial base growth.
