Cleidocranial dysplasia is a well-documented rare autosomal dominant skeletal dysplasia characterized by hypoplastic/aplastic clavicles, brachycephalic skull, patent sutures and fontanelles, midface hypoplasia, and abnormalities of dentition. Patients with cleidocranial dysplasia often complain about undesirable esthetic appearance of their forehead and skull. Notwithstanding many studies of molecular, genetics and skeletal abnormalities of this congenial disorder, there have been very few written reports of cranioplasty involving cleidocranial dysplasia. Thus, we report a rare case of successful cranioplasty using a modified split calvarial graft technique in patient with cleidocranial dysplasia.
Clavicle ; Cleidocranial Dysplasia* ; Dentition ; Forehead ; Genetics ; Humans ; Skull ; Sutures ; Transplants*

Adult ; Cleidocranial Dysplasia ; genetics ; pathology ; Female ; Humans ; Male ; Middle Aged

OBJECTIVE: To detect the genetic variant of a child with cleidocranial dysplasia (CCD) and to find out the causation of the illness. METHODS: Gene variant was identified by the second generation targeted sequencing and Sanger sequencing. RESULTS: The gene sequencing revealed that the RUNX2 gene had c.196C>T(p.Glu66*) nonsense variant, which was predicted to be a pathogenic variant according to the ACMG guidelines(PVS1+PS2). CONCLUSION The variant of c.196C > T in the RUNX2 gene may be the cause of the child with CCD, and the novel variant enriches the RUNX2 gene variant spectrum.
Asians/genetics* ; Child ; China ; Cleidocranial Dysplasia/genetics* ; Core Binding Factor Alpha 1 Subunit/genetics* ; Humans ; Mutation

OBJECTIVECleidocranial dysplasia (CCD) is a rare skeletal disease with autosomal dominant inheritance associated with mutation in RUNX 2. The authors report a Chinese girl with CCD in whom the mutation in RUNX 2 was identified.

METHODSClinical diagnosis was based on physical examination, radiological findings, and biochemical tests. For mutation detection, genomic DNA was extracted from peripheral blood using standard method. All 7 coding exons of RUNX 2 and their flanking intronic sequences were amplified by polymerase chain reaction (PCR), and the PCR products were then subjected to automatic DNA sequencing.

RESULTSThe affected girl showed typical clinical manifestations of CCD, including patent fontanelles, absent clavicles, short stature and dental anomalies. Direct sequencing of PCR-amplified fragments revealed a recurrent missense mutation, R190W (568 C > T), in RUNX 2. The mutation was further confirmed by Hae III restriction analysis.

CONCLUSIONA Chinese case of CCD was confirmed and the disease-causing mutation was linked to a recurrent point mutation in RUNX 2.

Cleidocranial Dysplasia ; genetics ; Core Binding Factor Alpha 1 Subunit ; genetics ; Female ; Humans ; Mutation

OBJECTIVE: To explore the genetic basis for a Chinese patient featuring cleidocranial dysplasia(CCD). METHODS: Genomic DNA was extracted from peripheral blood samples of the patient and his parents. Whole exome sequencing (WES) was carried out for the patient, and suspected variant was verified by Sanger sequencing. RESULTS: WES has identified a missense c.460G>T (p.Val154Phe) (GRCh37/hg19) variant of the RUNX2 gene. The variant was located in the Runt domain, a highly conserved region (PM1); it was not present in either the Genome Aggregation Database or the 1000 Genomes Project (PM2), and was predicted to have a deleterious effect on the gene product by multiple in silico prediction tools (PP3); the clinical phenotype of the patient was highly consistent with that of cleidocranial dysplasia (PP4). Furthermore, the variant was unreported in medical literature and was absent in both parents (PS2). Based on the American College of Medical Genetics and Genomics guidelines, the c.460 G>T variant of RUNX2 gene was predicted to be pathogenic (PS2+PM1+PM2+PP3+PP4). CONCLUSION The c.460G>T (p.Val154Phe) variant of the RUNX2 gene probably underlay the clinical phenotype in the patient. Above finding has enabled accurate diagnosis and expanded the spectrum of RUNX2 variants.
China ; Cleidocranial Dysplasia/genetics* ; Core Binding Factor Alpha 1 Subunit/genetics* ; Humans ; Mutation ; Whole Exome Sequencing

OBJECTIVE: To analyze the clinical features and pathogenic variant in a Chinese pedigree affected with cleidocranial dysplasia (CCD). METHODS: Clinical data of 8 patients from the pedigree was collected, including physical examination and X-ray images of head, face, spine, limbs, and mouth. Peripheral blood samples were collected from 6 affected members for the extraction of genomic DNA. The proband and other 3 patients were subjected to trio-whole exome sequencing. Candidate variant was verified by Sanger sequencing of the other 2 affected members from the pedigree. RESULTS: This pedigree has included 22 members (8 affected) from four generations. Genetic testing revealed that the proband has harbored a novel pathogenic variant of the RUNX2 gene [NM_001024630: c.1268_1277del (p.P425Afs*56)], which was inherited from her mother and carried by all affected members in the pedigree. The same variant was not detected among the unaffected members, suggesting co-segregation with the phenotype. CONCLUSION The c.1268_1277del (p.P425Afs*56) variant of the RUNX2 gene probably underlay the pathogenesis of CCD in this pedigree. Genetic testing has facilitated the definite diagnosis and enabled prenatal diagnosis.
Humans ; Pregnancy ; Female ; Cleidocranial Dysplasia/genetics* ; Pedigree ; Core Binding Factor Alpha 1 Subunit/genetics* ; Phenotype ; China ; Mutation

OBJECTIVE: To explore the clinical phenotypes and genetic diagnosis of 2 sporadic cases for cleidocranial dysplasia. METHODS: The clinical data of two cases of CCD admitted to the Third Affiliated Hospital of Zhengzhou University on December 16, 2021 and December 9, 2021 were analyzed retrospectively, and the whole exome sequencing (WES), chromosome microarray analysis and copy number variation sequencing were performed. RESULTS: The main ultrasonographic findings of the fetus had included poorly calcified skull bones, budging of parieto-occipital area, compression and deformation of skull, and loss of nasal bone. The infant's clinical phenotypes included delayed closure of anterior fontanelle, recurrent respiratory tract infection, growth retardation, and clavicular hypoplasia. By WES analysis, the fetus was found to harbor a heterozygous c.911_914delinsTTT variant of the RUNX2 gene, whilst the infant was found to harbor a heterozygous c.1008delT variant of the RUNX2 gene. Both variants were verified by Sanger sequencing to have occurred de novo. CONCLUSION For sporadic cases featuring cleidocranial dysplasia, prenatal ultrasonography is particularly important. Hypoplastic clavicle, skull calcification and nasal bone absence are the main features. Diagnosis should also be suspected for infants featuring growth retardation, recurrent respiratory tract infections and clavicular dysplasia. The identification of the c.911_914delinsTTT and c.1008delT variants of the RUNX2 gene has facilitated genetic counseling and prenatal diagnosis, and also expanded the mutational spectrum of the RUNX2 gene.
Female ; Humans ; Pregnancy ; Cleidocranial Dysplasia/genetics* ; Core Binding Factor Alpha 1 Subunit ; DNA Copy Number Variations ; Growth Disorders ; Retrospective Studies

BACKGROUNDCleidocranial 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.

METHODSWe made genetic testing on this sporadic Chinese case and identified a novel RUNX2 frameshift mutation: c.1111dupT. 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.

RESULTSRUNX2 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.

CONCLUSIONSWe identified a sporadic CCD patient carrying a novel insertion/frameshift mutation of RUNX2. This finding expanded our understanding of CCD-related phenotypes.

Adolescent ; Cell Nucleus ; metabolism ; Cleidocranial Dysplasia ; genetics ; Core Binding Factor Alpha 1 Subunit ; genetics ; Female ; Frameshift Mutation ; genetics ; Humans ; Microscopy, Fluorescence ; Mutation

OBJECTIVECleidocranial dysplasia (CCD) is a dominantly inherited skeletal dysplasia caused by mutations in the osteoblast-specific transcription factor-encoding gene, core binding factor α1 (CBFA1). Over 90 mutations in CBFA1 gene have been published to date in 500 independent cases of CCD, including missense mutations, deletions, insertions, frameshift, and splice mutations. However, mutational screening of the CBFA1 gene is still far from saturation, and more novel mutations will be identified to enrich the insights into the molecular basis for the pathogenesis of CCD. The aim of this study was to explore the clinical and image features and detect the mutations of CBFA1 gene in two CCD families.

METHODIn this study, the clinical features were investigated in two CCD families, radiological and CT examinations regarding osseous malformation were carried out over the entire body of these patients with CCD. Blood (2 ml) was drawn from all affected individuals, unaffected family members and one hundred unrelated normal controls, Genomic DNA was extracted from whole blood with PureGene DNA extraction kit and PCR was performed with eight pairs of PCR primers for exons 0 to 7 of the CBFA1 gene. The mutations of CBFA1 gene were screened in these two CCD families.

RESULT(1) The clinical features of patients with CCD include delayed closure of fontanelles, frontal bossing, dysplasia of clavicles, late tooth eruption, and other skeletal anomalies. X-ray and CT examination showed the bulging calvarium, patent fontanelles, wide cranial sutures, multiple Wormian bones, dental dysplasia or aplasia of clavicles. (2) Two mutations were identified, one is novel missense mutation (c.1259C > T[p.T420I]) in CBFA1 gene exon 7, other (c.577C > T[p.R193X]) was reported in Chinese cases with CCD for the first time.

CONCLUSION(1) The clinical and image features of patients in two CCD families include delayed closure of fontanelles, frontal bossing, dysplasia of clavicles, late tooth eruption, and other skeletal anomalies. (2) The T420I and R193X mutations of CBFA1 were reported, expanding the spectrum of CBFA1 mutations causing CCD.

Child ; Child, Preschool ; Cleidocranial Dysplasia ; genetics ; pathology ; Core Binding Factor Alpha 1 Subunit ; genetics ; DNA Mutational Analysis ; Exons ; Female ; Humans ; Male ; Mutation ; Pedigree ; Phenotype

OBJECTIVETo carry out genetic analysis on a child with developmental delay and multiple malformation.

METHODSThe karotypes of the child and her parents were analyzed with routine chromosomal G-banding. Their genomic DNA was analyzed with array comparative genomic hybridization (aCGH).

RESULTSThe karyotype of the proband was determined as 46,XX,del(6)(q22),inv(6)(p21.1q21), while no karyotypic abnormality was detected in her parents. aCGH has identified in the child a de novo 800 kb deletion encompassing the RUNX2 gene at 6p21.1 and a de novo 11.79 Mb deletion at 6q21-q22.31.

CONCLUSIONBoth of the de novo deletions are pathogenic. Deletion of the RUNX2 gene probably underlies the cleidocranial dysplasia in the patient, while the 6q21-q22.31 deletion may result in malformation of the brain.

Child, Preschool ; Chromosome Banding ; Chromosome Deletion ; Chromosomes, Human, Pair 6 ; Cleidocranial Dysplasia ; genetics ; Comparative Genomic Hybridization ; Core Binding Factor Alpha 1 Subunit ; genetics ; Female ; Genetic Testing ; Humans ; Karyotyping