RUNX2-related metaphyseal dysplasia with maxillary hypoplasia: A rare skeletal disorder resembling SFRP4-related Pyle disease.

Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly (MDMHB) is an ultra-rare skeletal dysplasia caused by heterozygous intragenic RUNX2 duplications, comprising either exons 3 to 5 or exons 3 to 6 of RUNX2. In this study, we describe a 14-year-old Belgian boy with metaphyseal dysplasia with maxillary hypoplasia but without brachydactyly. Clinical and radiographic examination revealed mild facial dysmorphism, dental anomalies, enlarged clavicles, genua valga and metaphyseal flaring and thin cortices with an osteoporotic skeletal appearance. Exome sequencing led to the identification of a de novo heterozygous tandem duplication within RUNX2, encompassing exons 3 to 7. This duplication is larger than the ones previously reported in MDMHB cases since it extends into the C-terminal activation domain of RUNX2. We review previously reported cases with MDMHB and highlight the resemblance of this disorder with Pyle disease, which may be explained by intersecting molecular pathways between RUNX2 and sFRP4. This study expands our knowledge on the genotypic and phenotypic characteristics of MDMHB and the role of RUNX2 in rare bone disorders.

Heterozygous pathogenic variants involving CBFB cause a new skeletal disorder resembling cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare skeletal dysplasia with significant clinical variability. Patients with CCD typically present with delayed closure of fontanels and cranial sutures, dental anomalies, clavicular hypoplasia or aplasia and short stature. Runt-related transcription factor 2 (RUNX2) is currently the only known disease-causing gene for CCD, but several studies have suggested locus heterogeneity. METHODS: The cohort consists of eight subjects from five unrelated families partially identified through GeneMatcher. Exome or genome sequencing was applied and in two subjects the effect of the variant was investigated at RNA level. RESULTS: In each subject a heterozygous pathogenic variant in CBFB was detected, whereas no genomic alteration involving RUNX2 was found. Three CBFB variants (one splice site alteration, one nonsense variant, one 2 bp duplication) were shown to result in a premature stop codon. A large intragenic deletion was found to delete exon 4, without affecting CBFB expression. The effect of a second splice site variant could not be determined but most likely results in a shortened or absent protein. Affected individuals showed similarities with RUNX2-related CCD, including dental and clavicular abnormalities. Normal stature and neurocognitive problems were however distinguishing features. CBFB encodes the core-binding factor ß subunit, which can interact with all RUNX proteins (RUNX1, RUNX2, RUNX3) to form heterodimeric transcription factors. This may explain the phenotypic differences between CBFB-related and RUNX2-related CCD. CONCLUSION: We confirm the previously suggested locus heterogeneity for CCD by identifying five pathogenic variants in CBFB in a cohort of eight individuals with clinical and radiographic features reminiscent of CCD.

Three-dimensional evaluation of dental characteristics in patients with Cleidocranial dysplasia.

BACKGROUND: Cleidocranial dysplasia (CCD) is an autosomal dominant hereditary disorder. Besides skeletal abnormalities, CCD is often associated with dental complications, such as multiple supernumerary teeth and permanent teeth impaction or delayed eruption. METHODS: Supernumerary teeth of axial, sagittal and coronal CBCT view was characterized in detail and 3D image reconstruction was performed. Number and location of teeth, morphology of supernumerary teeth, positional relationship between supernumerary and adjacent permanent teeth, direction of supernumerary teeth in CCD patients were analyzed. RESULTS: The mean age of the 3 CCD patients in this study was 16.7 years. Among 36 supernumerary teeth, the majority of them were identified as apical side located and lingual side located. Normal orientation was the most common type in this study, followed by sagittal orientation, and horizontal orientation. Horizontal orientation teeth were all distributed in the mandible. Supernumerary teeth exhibited significantly shorter crown and dental-root lengths, as well as smaller crown mesiodistal and buccolingual diameters (P < 0.01). There was no difference in the number of supernumerary teeth between the maxilla and mandible, and the premolars region had the largest number of supernumerary teeth and the incisor region had the smallest number. CONCLUSIONS: This study compares number and location of teeth, morphology of supernumerary teeth, positional relationship between supernumerary and adjacent permanent teeth and direction of supernumerary teeth, this study also provides a reference for the comprehensive evaluation of CCD patients before surgery.

A novel single-base deletion of the RUNX Family Transcription Factor 2 gene associated with cleidocranial dysplasia.

Cleidocranial dysplasia (CCD) is a rare, autosomal dominant hereditary disorder characterized by skeletal malformations and dental abnormalities. The purpose of this study was to explore the functional role of a novel mutation in the pathogenesis of CCD. Genomic DNA was extracted from peripheral blood mononuclear cells collected from family members of a Chinese patient with CCD. An analysis of their RUNX Family Transcription Factor 2 (RUNX2) gene sequences was performed by PCR amplification and Sanger sequencing. The function of the mutant RUNX2 was studied by bioinformatics, real-time PCR, western blotting, and subcellular localization analysis. Sanger sequencing identified a novel single-base deletion (NM_001024630.4:c.132delG;NP_001019801.3: Val45Trpfs* 99) in the RUNX2 gene present in the Chinese patient with CCD. In vitro, functional studies showed altered protein localization and increased expression of mutant RUNX2 mRNA and mutant Runt-related transcription factor 2 (RUNX2). Luciferase reporter assay demonstrated that the novel RUNX2 mutations significantly increased the transactivation activity of RUNX2 on the osteocalcin gene promoter. In conclusion, we identified a patient with sporadic CCD carrying a novel deletion/frameshift mutation of the RUNX2 gene and performed screening and functional analyses to determine the cause of the CCD phenotype. This study provides new insights into the pathogenesis of CCD.3.

Impact of Mechanical Strain and Nicotinamide on RUNX2-Deficient Osteoblast Mimicking Cleidocranial Dysplasia.

Cleidocranial dysplasia (CCD) is a rare genetic defect caused by a heterozygous mutation of runt-related transcription factor 2 (RUNX2), which is important for osteoblast and skeletal development. RUNX2-deficiency causes extra- and intra-oral malformations that often require orthodontic treatment. Nicotinamide (NAM) affects bone remodelling processes. As these are crucial for orthodontic therapy, NAM could improve orthodontic treatment in CCD patients. This study investigates the effect of NAM in control and RUNX2-deficient osteoblasts under mechanical strain mimicking orthodontic treatment. First, the optimal NAM concentration and the differences in the expression profile of control and RUNX2-deficient osteoblasts were determined. Subsequently, osteoblasts were exposed to tensile and compressive strain with and without NAM, and the expression of genes critically involved in bone remodelling was investigated. NAM increased the expression of bone remodelling genes. RUNX2-deficient osteoblasts expressed more receptor activator of NFkB ligand (RANKL) and interleukin-6 (IL6), but less colony-stimulating factor-1 (CSF1). Most of the positive effects of NAM on bone remodelling genes were impaired by mechanical loading. In conclusion, NAM stimulated osteoblast differentiation by increasing the expression of RUNX2 and regulated the expression of osteoclastogenic factors. However, the positive effects of NAM on bone metabolism were impaired by mechanical loading and RUNX2 deficiency.

Multidisciplinary prosthetic rehabilitation of an adult patient with cleidocranial dysplasia by using a rapid external distraction device: A clinical report.

The multidisciplinary treatment of a 41-year-old man with cleidocranial dysplasia is described. A rapid external distraction device was used to reposition the maxilla before the prosthodontic rehabilitation.

[Analysis of clinical phenotypes and genetic variants in two children with sporadic cleidocranial dysplasia].

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.

Chloroquine corrects enlarged lysosomes in FIG4 null cells and reduces neurodegeneration in Fig4 null mice.

Loss-of-function mutations of FIG4 impair the biosynthesis of PI(3,5)P2 and are responsible for rare genetic disorders including Yunis-Varón Syndrome and Charcot-Marie-Tooth Disease Type 4 J. Cultured cells deficient in FIG4 accumulate enlarged lysosomes with hyperacidic pH, due in part to impaired regulation of lysosomal ion channels and elevated intra-lysosomal osmotic pressure. We evaluated the effects of the FDA approved drug chloroquine, which is known to reduce lysosome acidity, on FIG4 deficient cell culture and on a mouse model. Chloroquine corrected the enlarged lysosomes in FIG4 null cells. In null mice, addition of chloroquine to the drinking water slowed progression of the disorder. Growth and mobility were dramatically improved during the first month of life, and spongiform degeneration of the nervous system was reduced. The median survival of Fig4 null mice was increased from 4 weeks for untreated mutants to 8 weeks with chloroquine treatment (p < 0.009). Chloroquine thus corrects the lysosomal swelling in cultured cells and ameliorates Fig4 deficiency in vivo. The improved phenotype of mice with complete loss of Fig4 suggests that chloroquine could be beneficial FIG2 in partial loss-of-function disorders such as Charcot-Marie-Tooth Type 4 J.

Hypophosphatasia and cleidocranial dysplasia-a case report and review of the literature: the role of the neurosurgeon.

Hypophosphatasia (HPT) and cleidocranial dysplasia (CCD) are rare genetic disorders characterized by both defective ossification and bone mineralization. Patients usually present with craniosynostosis and cranial defects which in many cases require surgical repair. There is only 1 reported case of combined HPT and CCD in the literature. Our reported case involves a 3.5-year-old girl with concomitant homozygous CCD and heterozygous HPT. The child had an extended cranial defect since birth which improved with the administration of Strensiq and was followed until preschool age. Bone defects were relatively minor on revaluation. Due to the limited final defect, we decided not to intervene. In HPT-CCD patients, bone defects are overestimated due to osteomalacia, and thus, management strategy should be less aggressive. They should undergo surgical repair with cranioplasty with the use of cement and/or titanium meshes in case of extended final defects.

Identification of a familial cleidocranial dysplasia with a novel RUNX2 mutation and establishment of patient-derived induced pluripotent stem cells.

Cleidocranial dysplasia (CCD) is an autosomal dominant hereditary disease associated with the gene RUNX2. Disease-specific induced pluripotent stem cells (iPSCs) have emerged as a useful resource to further study human hereditary diseases such as CCD. In this study, we identified a novel CCD-specific RUNX2 mutation and established iPSCs with this mutation. Biopsies were obtained from familial CCD patients and mutation analyses were performed through Sanger sequencing and next generation sequencing. CCD-specific human iPSCs (CCD-hiPSCs) were established and maintained under completely defined serum, feeder, and integration-free condition using a non-integrating replication-defective Sendai virus vector. We identified the novel mutation RUNX2_c.371C>G and successfully established CCD-hiPSCs. The CCD-hiPSCs inherited the same mutation, possessed pluripotency, and showed the ability to differentiate the three germ layers. We concluded that RUNX2_c.371C>G was likely pathogenic because our results, derived from next generation sequencing, are supported by actual clinical evidence, familial tracing, and genetic data. Thus, we concluded that hiPSCs with a novel CCD-specific RUNX2 mutation are viable as a resource for future studies on CCD.

Induced pluripotent stem cells from homozygous Runx2-deficient mice show poor response to vitamin D during osteoblastic differentiation.

Cleidocranial dysplasia (CCD) is a hereditary disorder associated with skeletal dysplasia and dental abnormalities. CCD arises from heterozygous loss of function mutations in the Runt-related transcription factor 2 (RUNX2) gene. Osteoporosis is often observed in CCD patients and conventional vitamin D supplementation is recommended. However, sufficient evidences have not been presented yet. This study investigated the role of RUNX2 in osteoblastic differentiation and sought to identify potential target genes for the treatment of osteoporosis associated with CCD, using induced pluripotent stem cell (iPSC) technology. We successfully established Runx2-/-, Runx2+/- and wild-type miPSCs from litter-matched mice and found poor Vdr expression in Runx2-/-cells. Significant down-regulation of osteoblastic differentiation in Runx2-/- miPSCs was observed. Gene expression array revealed unexpected results such as remarkable increase of Rankl expression and decrease of Vdr in Runx2-/- cells. Insufficient response to vitamin D in Runx2-/- cells was also observed. Our results suggest that RUNX2 functions as a regulator of Rankl and Vdr and thereby controls bone density. These findings also suggest that conventional vitamin D supplementation may not be as effective as previously expected, in the treatment of osteoporosis associated with CCD, and that inhibiting RANKL function might be worth considering as an alternative treatment strategy.

An overview of the intraoral features and craniofacial morphology of growing and adult Japanese cleidocranial dysplasia subjects.

BACKGROUND: Orthodontic treatment for cleidocranial dysplasia (CCD) requires an understanding of the nature of the retained deciduous teeth, supernumerary teeth, delayed eruption of the permanent teeth, and craniofacial morphology from childhood to adulthood. This study aimed to provide an overview of the intraoral and craniofacial characteristics of growing and adult Japanese CCD subjects. METHODS: We assessed cross-sectionally the intraoral features of 28 CCD subjects (males, 15.3 ± 7.0 years; females, 15.2 ± 5.1 years) using orthopantomograms and photographs. Mean facial diagrams (profilograms) of 3 age groups (5-10 years, 11-14 years, over 15 years: adult) were constructed, and linear and angular measurements of 2 age groups (under 15 years, adult) were performed by using cephalograms. The data were compared with Japanese standards. RESULTS: A mean of 11.7 and 8.4 retained deciduous teeth, 10.4 and 15.8 erupted permanent teeth were observed in the adult males and females, and a mean of 6.8 and 5.3 supernumerary teeth were observed in all males and females, respectively. A positive correlation was found between the number of supernumerary teeth and the age at initial visit. Cephalometric analysis showed an average to anteriorly positioned maxilla, a tendency for counter-clockwise rotation of the ramus, and a prognathic mandible in all groups. CONCLUSIONS: The number of supernumerary teeth increased with age. The maxilla was average to anteriorly positioned, and the mandible was counter-clockwise rotated and prognathic for all groups. These characteristic craniofacial morphologies and changes of intraoral conditions at different ages in CCD patients should be considered when proposing rational orthodontic treatment plans.

[Analysis of clinical phenotype and genetic variant in a Chinese pedigree affected with cleidocranial dysplasia].

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.

[Identification of c.196C>T nonsense RUNX2 variant in a Chinese patient with cleidocranial dysplasia].

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.

Detection and diagnosis of cleidocranial dysplasia by panoramic radiography: a retrospective study.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare and underdiagnosed congenital disorder in dentistry. The purpose of this study was to illustrate and quantify the maxillofacial bone abnormalities detected on panoramic radiographs from a relatively large retrospective case series and to provide a series of diagnostic references for dentists to indicate the presence of disease and help in making an early and accurate diagnosis. METHODS: The dental panoramic radiographs of thirty CCD patients aged 11 to 45 years (18 males and 12 females) were examined retrospectively. The dentition states, including supernumerary teeth and impacted teeth, were recorded. Twelve quantified measurements were adopted to determine the abnormalities of maxillofacial bones, including the degree of the zygomatic arch downward bend, bicondylar breadth, ramal height, mandibular height, mandibular aspect ratio, mandibular body height, condylar height, coronoid height, distance between the coronoid process and the condyle, bigonial width, gonial angle and best-fit gonial circle diameter. The Wilcoxon rank-sum test was used to compare the findings of the CCD patients with those of their matched controls (n = 300). RESULTS: Supernumerary teeth were detected in 27 patients (90.0%), and all 30 patients presented impacted teeth. Compared to the matched controls, the CCD patients had a significantly larger degree of zygomatic arch downward bend (ZAD), a larger diameter of the best-fit gonial circle (BGC), and a shorter distance between the coronoid process and the condyle (DCC) in panoramic radiographs (P < 0.001). According to the reference cutoff values established from the 5th or 95th percentile of the measurements in the control group, ZAD higher than 6.90 mm, DDC less than 22.37 mm and BGC higher than 52.41 mm were significantly associated with the CCD features identified. Other panoramic measurements were not significantly different between the two groups. CONCLUSIONS: Panoramic radiographs had great value in the diagnosis of CCD. In this study, we identified some dental and maxillofacial features on panoramic radiographs from a relatively large retrospective case series of CCD. A series of reliable quantitative indicators were provided for dentists that can indicate the presence of disease and improve the diagnostic specificity.

Clinical, radiographic, and genetic observations in 2 families with cleidocranial dysplasia.

The clinical, radiographic, and molecular alterations in 7 individuals belonging to 2 families with clinical characteristics of cleidocranial dysplasia (CCD) were investigated. The patients underwent karyotype and genetic sequencing examinations. Cytogenetic analysis did not demonstrate any alterations. The next-generation sequencing technique employed for the molecular analysis revealed sequence variations in the RUNX2 gene: c.568C>T (p.Arg190Trp) in exon 4 in family A and c.1205del (p.Pro402Argfs*82) in exon 9 in family B. Incomplete closure of anterior fontanels, hypoplastic clavicles, and dental changes were observed in all 7 patients. Uncommon clinical findings, such as partial hearing loss and bilateral clavicular agenesis, were noted in some patients. According to the literature consulted, this is the first time that the total absence of the pubic bone in a study subject is being reported. The variable expression among individuals of the same family and between families A and B suggests the absence of a genotype-phenotype relationship. Early diagnosis allows the dentist to minimize the effects of changes associated with CCD by monitoring and providing appropriate treatment, and the identification of genetic sequence variations enables appropriate family genetic counseling.

Runx2 regulates cranial suture closure by inducing hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in suture mesenchymal cells.

Cleidocranial dysplasia (CCD, #119600), which is characterized by hypoplastic clavicles, open fontanelles, supernumerary teeth and a short stature, is caused by heterozygous mutations in RUNX2. However, it currently remains unclear why suture closure is severely impaired in CCD patients. The closure of posterior frontal (PF) and sagittal (SAG) sutures was completely interrupted in Runx2+/- mice, and the proliferation of suture mesenchymal cells and their condensation were less than those in wild-type mice. To elucidate the underlying molecular mechanisms, differentially expressed genes between wild-type and Runx2+/- PF and SAG sutures were identified by microarray and real-time reverse transcription polymerase chain reaction analyses. The expression of hedgehog, Fgf, Wnt and Pthlh signaling pathway genes, including Gli1, Ptch1, Ihh, Fgfr2, Fgfr3, Tcf7, Wnt10b and Pth1r, which were directly regulated by Runx2, was reduced in the sutures, but not the calvarial bone tissues of Runx2+/- mice. Bone formation and suture closure were enhanced in an organ culture of Runx2+/- calvariae with ligands or agonists of hedgehog, Fgf, Wnt and Pthlh signaling, while they were suppressed and suture mesenchymal cell proliferation was decreased in an organ culture of wild-type calvariae with their antagonists. These results indicate that more than a half dosage of Runx2 is required for the proliferation of suture mesenchymal cells, their condensation and commitment to osteoblast-lineage cells, and the induction of hedgehog, Fgf, Wnt and Pthlh signaling pathway gene expressions in sutures, but not in calvarial bone tissues, and also that the activation of hedgehog, Fgf, Wnt and Pthlh signaling pathways is necessary for suture closure.

Skeletal and molecular findings in 51 Cleidocranial dysplasia patients from Turkey.

Loss or decrease of function in runt-related transcription factor 2 encoded by RUNX2 is known to cause a rare autosomal-dominant skeletal disorder, cleidocranial dysplasia (CCD). Clinical spectrum and genetic findings in 51 CCD patients from 30 unrelated families are herein presented. In a majority of the patients, facial abnormalities, such as delayed fontanel closure (89%), parietal and frontal bossing (80%), metopic groove (77%), midface hypoplasia (94%), and abnormal mobility of shoulders (90%), were recorded following clinical examination. In approximately one-half of the subjects, wormian bone (51%), short stature (43%), bell-shaped thorax (42%), wide pubic symphysis (50%), hypoplastic iliac wing (59%), and chef's hat sign (44%) presented in available radiological examinations. Scoliosis was identified in 28% of the patients. Investigation of RUNX2 revealed small sequence alterations in 90% and gross deletions in 10% of the patients; collectively, 23 variants including 11 novel changes (c.29_30insT, c.203delAinsCG, c.423 + 2delT, c.443_454delTACCAGATGGGAinsG, c.505C > T, c.594_595delCTinsG, c.636_637insC, c.685 + 5G > A, c.1088G > T, c.1281delC, Exon 6-9 deletion) presented high allelic heterogeneity. Novel c.29_30insT is unique in affecting the P1-driven long isoform of RUNX2, which is expected to disrupt the N-terminal region of RUNX2; this was shown in two unrelated phenotypically discordant patients. The clinical findings highlighted mild intra-familial genotype-phenotype correlation in our CCD cohort.

Posterior fossa subdural hematoma in a neonate with cleidocranial dysostosis after a spontaneous vaginal delivery: a case report.

BACKGROUND: Cleidocranial dysostosis (CCD) is an anomaly characterized by delayed closure of the cranial sutures, midface hypoplasia, moderately short stature, hypoplastic or aplastic clavicles, dental abnormalities, and other complications. CASE PRESENTATION: We report a case of posterior fossa subdural hematoma (PFSDH) after vaginal delivery in a neonate with CCD, which presented with several clinical symptoms such as apnea, vomiting, and bradycardia. Our patient, who had a family history of CCD, developed apnea and vomiting shortly after birth; PFSDH was detected by head computed tomography, and the patient recovered well following standard medical treatment. CONCLUSION: The prognosis of intracranial hemorrhage in neonates with CCD is generally poor. In neonates, PFSDH occurs by the following mechanism: the distortion of the infant's cranium during delivery, by the strong force, causes elongation of the falx and angulation of the tentorium that leads to tears in the posterior fossa venous structures, which then cause bleeding into the subdural space. In CCD, the forces occurring during vaginal delivery may causeexcessive distortion of the fragile skull. An awareness of CCD is hence important to avoid vaginal delivery in prenatally diagnosed CCD cases with a family history of CCD.

Identification of a Novel Mutation in the Runt-Related Transcription Factor 2 Gene in a Chinese Family With Cleidocranial Dysplasia.

ABSTRACT: Cleidocranial dysplasia (CCD) is an uncommon autosomal dominant disease, characterized by hypoplasia of clavicles, delayed fontanelle closure, dental anomalies, and short stature. It has been reported in the literature that the pathogenic variants of Runt-related transcription factor 2 (RUNX2) gene are correlated with CCD patients.Here, we report a consanguineous Chinese family with 2 patients suffering from CCD, presenting similar skeleton and dentition malformation. Upon whole-exome sequencing, 52863 variants were detected in the propositus. Based on the genotype phenotype correlation, a frameshift deletion c.1554delG p.(Trp518Cysfs∗61), located in exon 8 of RUNX2, remained after filtration. For Sanger sequencing, all exons of the RUNX2 gene in members of this Chinese family were amplified by polymerase chain reaction. Mutation mentioned above was confirmed in the propositus and his mother, which has not been reported previously and cannot be found in the publicly available databases. The present study expands the pathogenic variant spectrum of RUNX2 gene and contributes to molecular diagnosis.