CLEIDOCRANIAL DYSOSTOSIS
CLEIDOCRANIAL DYSPLASIA, FORME FRUSTE, DENTAL ANOMALIES ONLY, INCLUDED
CLCD CLEIDOCRANIAL DYSPLASIA, FORME FRUSTE, WITH BRACHYDACTYLY, INCLUDED
CCD
The main clinical features of CCD include persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, dental ... The main clinical features of CCD include persistently open skull sutures with bulging calvaria, hypoplasia or aplasia of the clavicles permitting abnormal facility in apposing the shoulders, wide pubic symphysis, short middle phalanx of the fifth fingers, dental anomalies, and often vertebral malformation. See 168550 for a discussion of the combination of cleidocranial dysplasia and parietal foramina. Pycnodysostosis (265800) and mandibuloacral dysplasia (248370) are disorders to be considered in the differential diagnosis of cleidocranial dysplasia. Acroosteolysis and bone sclerosis with tendency to fracture are differentiating features of pycnodysostosis. Mundlos (1999) provided a review of the clinical features of cleidocranial dysplasia and the molecular basis of this disorder.
One of the most colorful families was described by Jackson (1951). The condition occurred in many descendants of a Chinese man named Arnold who embraced the Mohammedan religion and 7 wives in South Africa. Jackson (1951) was able ... One of the most colorful families was described by Jackson (1951). The condition occurred in many descendants of a Chinese man named Arnold who embraced the Mohammedan religion and 7 wives in South Africa. Jackson (1951) was able to trace 356 descendants, of whom 70 were affected by the 'Arnold head.' For translation of original description by Marie and Sainton (1898), see Bick (1968). Ramesar et al. (1996) estimated that more than 1,000 descendants of the first progenitor now have the disorder. A family with delayed eruption of deciduous and permanent teeth reported by Arvystas (1976) probably had cleidocranial dysplasia. Dore et al. (1987) described a 34-year-old woman with cleidocranial dysostosis and scoliosis diagnosed at age 13 years. The scoliosis continued to progress after skeletal maturation. Syringomyelia was diagnosed at the age of 34. The authors noted reports of 2 previous patients with cleidocranial dysostosis and syringomyelia and suggested that this association may be a more common problem than generally recognized. Jensen (1990) studied development in 7 males and 10 females, aged 5 to 46 years, with CCD; 11 were followed longitudinally. Height and radius length were decreased, especially in females. Longitudinal data showed growth retardation and slightly retarded skeletal maturation throughout childhood. The metacarpophalangeal pattern profile demonstrated great variation in bone length, presumably resulting from extra epiphyses in metacarpals II and V and from multiple cone-shaped epiphyses. Jensen (1990) concluded that CCD is a generalized skeletal dysplasia. Chitayat et al. (1992) described the range of variability in affected members in 3 generations of a family. The propositus presented with respiratory distress due to a narrow thorax. The clavicles were hypoplastic with discontinuity in the central portions. A 17-year-old aunt of the proposita showed large fontanels and multiple wormian bones as well as a wide symphysis pubis with hypoplasia of the iliac bones. The 25-year-old mother of the proposita showed typical hand abnormalities by x-ray: thin metacarpal and metatarsal diaphyses of digits 2 to 5 and short middle phalanx of fingers 2 and 5. The grandmother likewise showed wormian bones. On the basis of a review of 13 patients, Reed and Houston (1993) concluded that underossification of the hyoid bone could be added to the delayed ossification that affects the skull, teeth, pelvis, and extremities in CCD.
To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, Zhou et al. (1999) studied 26 independent cases of CCD, and a total of 16 new mutations were identified in 17 families. Most mutations were ... To correlate CBFA1 mutations in different functional domains with the CCD clinical spectrum, Zhou et al. (1999) studied 26 independent cases of CCD, and a total of 16 new mutations were identified in 17 families. Most mutations were de novo missense mutations that affected conserved residues in the runt domain and completely abolished both DNA binding and transactivation of a reporter gene. These, and mutations that resulted in premature termination in the runt domain, produced a classic CCD phenotype by abolishing transactivation of the mutant protein with consequent haploinsufficiency. Zhou et al. (1999) further identified 3 putative hypomorphic mutations that resulted in a clinical spectrum including classic and mild CCD, as well as an isolated dental phenotype characterized by delayed eruption of permanent teeth (600211.0010). Functional studies showed that 2 of the 3 mutations were hypomorphic in nature and 2 were associated with significant intrafamilial variability in expressivity, including isolated dental anomalies without the skeletal features of CCD. Together these data showed that variable loss of function due to alterations in the runt and C-terminal proline/serine/threonine-rich (PST) activation domains of CBFA1 may give rise to clinical variability, including classic CCD, mild CCD, and isolated primary dental anomalies.
Mundlos et al. (1997) found the linkage to 6p21 in studies of 3 additional large families with 39 affected members. The region in which the refined localization placed the gene was covered by 14 yeast artificial chromosomes (YACs). ... Mundlos et al. (1997) found the linkage to 6p21 in studies of 3 additional large families with 39 affected members. The region in which the refined localization placed the gene was covered by 14 yeast artificial chromosomes (YACs). Three known genes were identified within the contig: TCTE1 (186975), MUT (609058), and CBFA1 (600211). CBFA1 was a reasonable candidate gene for CCD because a member of the 'runt' family had previously been described as a bone-specific nuclear-matrix-binding transcription factor. By fluorescence in situ hybridization to YACs, they confirmed the presence of a deletion on 6p in 1 family and enabled them to narrow the region to approximately 1.5 Mb. They also studied the patient with a pericentric inversion involving 6p21-q16 previously documented by Nienhaus et al. (1993) and found results supporting the assignment. Thus, in some families, the phenotype segregated with deletions, resulting in heterozygous loss of CBFA1. In other families, Mundlos et al. (1997) found insertion, deletion, and missense mutations leading to translational stop codons in the DNA-binding domain or in the C-terminal transactivating region of the CBFA1 protein (see, e.g., 600211.0001; 600211.0003). In-frame expansion of a polyalanine stretch segregated in an affected family with brachydactyly and minor clinical findings of CCD; see 600211.0003. Heterozygous loss of function of CBFA1 appeared to be sufficient to produce CCD. In 29 patients with CCD from 19 unrelated families, Baumert et al. (2005) sequenced the RUNX2 gene and identified 12 different RUNX2 mutations. They examined phenotypic data using homogeneity analysis and observed mild to full-blown expression of the CCD phenotype, with intrafamilial clinical variability. Baumert et al. (2005) commented that homogeneity analysis simplified grouping the patients into distinct entities, but noted that the analysis separated individuals with the same mutation, emphasizing the clinical variability within the patient cohort. El-Gharbawy et al. (2010) studied a 7-year-old boy with CCD complicated by severe progressive kyphoscoliosis, who also displayed features of hypophosphatasia (see 241500), including Bowdler spurs, severe osteopenia, and low alkaline phosphatase. After no RUNX2 mutation was found by sequencing, the authors performed array CGH and identified a 50- to 70-kb deletion that predicted a disruption of the C terminus of RUNX2, encompassing the coding sequence for amino acids 327 to 521 and involving the SMAD 1,2,3,5 binding sites and the nuclear matrix targeting signal (NMTS) regions. El-Gharbawy et al. (2010) emphasized the need to search for deletions when sequencing of the target gene is normal, and noted that the C-terminal region of RUNX2 appears to play an integral role in human osteogenesis and osteoblast differentiation.
Cleidocranial dysplasia (CCD) affects most prominently those bones derived from intramembranous ossification, such as the cranium and the clavicles, although bones formed through endochondral ossification can also be affected. Diagnosis is based on clinical and radiographic findings. ...
DiagnosisClinical DiagnosisCleidocranial dysplasia (CCD) affects most prominently those bones derived from intramembranous ossification, such as the cranium and the clavicles, although bones formed through endochondral ossification can also be affected. Diagnosis is based on clinical and radiographic findings. The most prominent clinical findings in CCD:Abnormally large, wide-open fontanels at birth that may remain open throughout life. The wide-open metopic suture results in separation of the frontal bones by a metopic groove. The forehead is broad and flat; the cranium is brachycephalic.Mid-face hypoplasiaAbnormal dentition, including delayed eruption of secondary dentition, failure to shed the primary teeth, variable numbers of supernumerary teeth along with dental crowding, and malocclusionClavicular hypoplasia, resulting in narrow, sloping shoulders that can be apposed at the midline (see Figure 1)Hand abnormalities such as brachydactyly, tapering fingers, and short, broad thumbsNormal intellect in individuals with typical CCDFigureFigure 1. Shoulders in an individual with clavicular hypoplasia may be brought to the midline. The most prominent radiographic findings in CCD:CraniumWide-open sutures, patent fontanels, presence of wormian bones (small sutural bones)Delayed ossification of the skullPoor or absent pneumatization of the paranasal, frontal, and mastoid sinusesImpacted, crowded teeth; supernumerary teethThorax (Figure 2)Cone-shaped thorax with narrow upper thoracic diameterClavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral and middle thirds of the clavicle are more commonly affected (see Figure 2).Hypoplastic scapulaePelvisDelayed ossification of the pubic bone, with wide pubic symphysisHypoplasia of the iliac wingsWidening of the sacroiliac jointsLarge femoral neck and large epiphysesHands (Figure 3)Pseudoepiphyses of the metacarpal and metatarsal bones, which may result in a characteristic lengthening of the second metacarpal (see Figure 3) Hypoplastic distal phalangesDeformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphysesOther. Osteopenia with evidence of decreased bone mineral density by DEXA in some individuals is a nonspecific finding.FigureFigure 2. Chest x-ray demonstrates clavicular hypoplasia. FigureFigure 3. Hand x-ray of a 2.5 year-old male with cleidocranial dysplasia a. Notice pseudoepiphyses at the bases of the second and third metacarpals with accessory physes seen at the base of the fourth and fifth metacarpals. b. Cone-shaped (more...)TestingChromosome analysis. On occasion individuals with CCD have cytogenetically visible complex chromosome rearrangements [Purandare et al 2008].Molecular Genetic TestingGene. To date, RUNX2 (CBFA1) is the only gene in which mutation is known to cause CCD.Evidence for locus heterogeneity. Although not all cases clinically diagnosed as CCD have mutations in RUNX2, there is little additional evidence for locus heterogeneity. Clinical testingSequence analysis. Sequence analysis of genomic DNA of the coding region of RUNX2 detects mutations in close to 70% of individuals with a clinical diagnosis of CCD. The mutations in most families are unique.Deletion/duplication analysis. Individuals with the CCD phenotype and additional findings including developmental delay may have deletion of all or part of the RUNX2 gene as well as neighboring genes. Microdeletions may be found in up to 13% of individuals with normal results on sequence analysis [Mendoza-Londono & Lee, unpublished observation of 40 individuals with CCD phenotype]. These deletions can be detected by numerous methods (see Table 1). Table 1. Summary of Molecular Genetic Testing Used in Cleidocranial DysplasiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityRUNX2Sequence analysis Missense and nonsense mutations, small insertions or deletions, exon-skipping mutations 60%-70%ClinicalDeletion / duplication analysis 2, 3 Large microdeletions involving RUNX2 and contiguous gene(s) 413% 51. The ability of the test method used to detect a mutation that is present in the indicated gene2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment. 3. Probes spanning the RUNX2 sequence are included in some commercially available CMA platforms; this approach may identify clinically relevant but unanticipated abnormalities. FISH with specific probes that contain part of the RUNX2 sequence will also detect microdeletions. RUNX2 is covered by three partially overlapping clones that can be used for FISH: RP11-166H4, RP11-244F24, and RP11-342L7.4. Individuals with these deletions may have the CCD phenotype and additional findings including developmental delay.5. 13% of individuals with normal results on sequence analysis Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis in a probandWhen the diagnosis of CCD is suspected, the clinician should request a skeletal survey that includes: (1) anteroposterior (AP) and lateral projections of the skull and thorax; (2) AP of the pelvis; (3) lateral of the lumbar spine; and (4) AP of the long bones, hands, and feet.Individuals with atypical features and developmental delay should have a karyotype in order to evaluate for visible deletions or rearrangements involving the RUNX2 locus at 6p21. Molecular genetic testing is appropriate for diagnostic confirmation if the clinical findings do not meet clinical and radiologic diagnostic criteria.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersTo date, no other phenotypes have been associated with mutations in RUNX2.
Cleidocranial dysplasia (CCD) is a skeletal dysplasia characterized by delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and multiple dental abnormalities. Jackson [1951] described an extensive family with CCD. More recently, Cooper et al [2001] recorded the natural history of 90 affected individuals and 56 first- and second-degree relatives. ...
Natural HistoryCleidocranial dysplasia (CCD) is a skeletal dysplasia characterized by delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and multiple dental abnormalities. Jackson [1951] described an extensive family with CCD. More recently, Cooper et al [2001] recorded the natural history of 90 affected individuals and 56 first- and second-degree relatives. Manifestations range from isolated dental anomalies to fully manifesting disease with poorly ossified cranium and absent clavicles [Golan et al 2000]. The phenotype may vary among individuals in the same family even though they have the same mutation. Males and females are affected equally.The main medical problems identified in individuals with CCD include the following:Height. Individuals with CCD are shorter than their unaffected sibs:Males are on average six inches shorter than their unaffected brothers and have an average height of 165 cm (±8 cm). Females are on average three inches shorter than their unaffected sisters and have an average height of 156 cm (±10 cm) [Cooper et al 2001].Skeletal/orthopedic problems. Individuals with CCD are more likely to have other bone-related problems: Pes planus (flat feet) in 57%Genu valgum (knock-knee deformity) in 28% Scoliosis in 18% [Cooper et al 2001]Other less common orthopedic problems include joint dislocation at the shoulder and elbow.ENT complications. Recurrent sinus infections and other upper-airway complications are observed significantly more often in individuals with CCD than in the general population. Conductive hearing loss occurs in 39% of affected individuals. Individuals with CCD of any age are more likely to have recurrent ear infections.Dental complications. Up to 94% of persons with CCD have dental findings including supernumerary teeth (they often do not lose their primary teeth) and eruption failure of the permanent teeth [Golan et al 2003]. The most consistent dental findings in individuals with CCD are the presence of the second permanent molar with the primary dentition (80%), wide spacing in the lower incisor area, supernumerary tooth germs (70%), and parallel-sided ascending rami [Cooper et al 2001, Golan et al 2003, Golan et al 2004]. Individuals with CCD are more likely to have an underbite and to have cysts in their gums that usually form around extra teeth [McNamara et al 1999].Obstetric complications. The primary cesarean section rate among women with CCD is 69%, which is higher than in controls [Cooper et al 2001].Development. Intelligence is normal in individuals with classic CCD. Children under age five years may show mild motor delay, particularly in gross motor abilities. This delay may be associated with orthopedic complications such as flat feet and knock-knees. No significant differences are observed among children in grade school.
Although the spectrum of phenotypic variability in CCD ranges from primary dental anomalies to all CCD clinical features plus osteoporosis, no clear phenotype-genotype correlation has been established [Otto et al 2002]....
Genotype-Phenotype CorrelationsAlthough the spectrum of phenotypic variability in CCD ranges from primary dental anomalies to all CCD clinical features plus osteoporosis, no clear phenotype-genotype correlation has been established [Otto et al 2002].All 24 Japanese individuals evaluated by Yoshida et al [2002] had the classic CCD phenotype, including hypoplastic clavicles and open sutures; in contrast, skeletal and dental findings demonstrated significant genotype-phenotype correlation. They also showed a direct correlation between (1) final height and residual transactivation activity of RUNX2, mediated by the runt domain, with an important additional effect given the individual's genetic background; and (2) the number of supernumerary teeth and the degree of short stature (i.e., the more supernumerary teeth, the shorter the individual).Mutations that result in premature termination upstream or within the runt domain produce classic CCD by abolishing the transactivation activity of the mutant protein with consequent haploinsufficiency. Hypomorphic mutations (Arg391X, Thr200Ala, and 90insC) result in a clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD to mild CCD to classic CCD. Intrafamilial variability is significant [Zhou et al 1999].Missense mutations cluster at arginine 225 (Arg225) of the RUNX2 protein, a critical residue for RUNX2 function. In vitro studies have shown that Arg225 mutations interfere with nuclear accumulation of RUNX2 protein. In addition, a frameshift mutation in codon 402 has been associated with osteoporosis leading to recurrent bone fractures and scoliosis reflecting the role of RUNX2 protein in the maintenance of adult bone [Quack et al 1999].
Other conditions share some characteristics with CCD. The fact that similar skeletal elements are affected suggests that some of these conditions may result from mutations in genes that affect the action of RUNX2 on its downstream targets. Most notable is association of deletions of CBF beta (CBFB) with wide-open fontanels and short clavicles [Goto et al 2004]. Because CBFB forms a heterodimer with RUNX2 to activate transcription of downstream targets, haploinsufficiency for this gene would explain the similarity in the phenotypes....
Differential DiagnosisOther conditions share some characteristics with CCD. The fact that similar skeletal elements are affected suggests that some of these conditions may result from mutations in genes that affect the action of RUNX2 on its downstream targets. Most notable is association of deletions of CBF beta (CBFB) with wide-open fontanels and short clavicles [Goto et al 2004]. Because CBFB forms a heterodimer with RUNX2 to activate transcription of downstream targets, haploinsufficiency for this gene would explain the similarity in the phenotypes.Crane-Heise syndrome (OMIM 218090) is a rare disorder characterized by a large head, poorly mineralized calvarium, cleft lip and palate, low-set dysplastic ears, hypoplastic clavicles and scapulae, agenesis of some cervical vertebrae, and genital hypoplasia. Inheritance may be autosomal recessive. Mandibuloacral dysplasia (MADA: OMIM 248370; MADB: OMIM 608612) is a progressive disorder characterized by short stature, delayed closure of cranial sutures, mandibular hypoplasia, and dysplastic clavicles. The scalp hair becomes sparse by the third decade and some individuals develop alopecia. The joints become progressively stiff; radiographs reveal acroosteodysplasia of the fingers and toes, with delayed ossification of the carpal bones. Osteolysis of the mandibular body and ramus results in micrognathia. In adolescence, dental crowding is observed; hypoplastic roots lead to early tooth loss. The skin is atrophic with decreased subcutaneous fat. Several individuals developed a hyperpigmented rash over the trunk and hyperkeratotic papular lesions of the extremities. MAD is associated with mutations in LMNA or ZMPSTE24. Inheritance is autosomal recessive.Pycnodysostosis (PYCD: OMIM 265800) is caused by mutations in the gene that encodes cathepsin K, a lysosomal protease excreted by the osteoclasts for bone matrix degradation. PYCD is characterized by short stature, osteopetrosis with increased bone fragility, short terminal phalanges, and failure of closure of the cranial sutures with persistence of an open fontanel. Radio-opacity of all bones is increased because of increased density of the trabecular bone but not the cortices. Inheritance is autosomal recessive.Yunis Varon syndrome (OMIM 216340) is characterized by prenatal growth deficiency, wide-open fontanels and sutures, unusual mineralization of the skull, and hypoplastic clavicles. The thumbs and great toes are hypoplastic or absent. Inheritance is autosomal recessive.CDAGS syndrome (OMIM 603116) is characterized by craniosynostosis, delayed closure of the fontanels, cranial defects, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption. It brings together the apparently opposing pathophysiologic and developmental processes of accelerated suture closure and delayed ossification [Mendoza-Londono et al 2005]. Inheritance is autosomal recessive.Hypophosphatasia is characterized by a generalized defect of mineralization with delayed ossification of multiple skeletal elements. Children with the infantile form may present with very poorly mineralized cranium, widened cranial sutures, short ribs, and narrow thorax. The alkaline phosphatase activity in serum and tissues is very low [Morava et al 2002]. In one report, an individual with severe CCD was initially thought to have hypophosphatasia [Unger et al 2002]. Hypophosphatasia is caused by mutations in ALPL, the gene encoding alkaline phosphatase. Inheritance is autosomal recessive.Parietal foramina with cleidocranial dysplasia (PFMCCD) is a distinct clinical entity with parietal foramina, mild craniofacial dysmorphisms, and clavicular hypoplasia. This condition is a manifestation of mutations in MSX2 and is not associated with the dental abnormalities seen in classic CCD [Garcia-Minaur et al 2003]. (See Enlarged Parietal Foramina.) Chromosomal abnormalities. Brueton et al [1992] described apparent CCD associated with abnormalities of 8q22 in three individuals. The first index case had at birth micrognathia, a large anterior fontanel with a wide sagittal suture, and a narrow upper thorax. X-rays at age 27 months showed wormian bones in the skull, underdevelopment of the maxillary bones, and bilateral hypoplastic clavicles. The child's mother had similar physical characteristics, with bilateral hypoplasia of clavicles, micrognathia, and short stature. Cytogenetic studies showed the balanced translocation 46,XX, t(8;10)(q22.1;p12.3).The third individual, the product of non-consanguineous parents, was noted at age four months to have a small central palatal cleft, large anterior fontanel, and wide sagittal suture. Her clavicles were rudimentary and hypoplastic. Cranial x-ray revealed wormian bones and micrognathia. Cytogenetic analysis showed a partial duplication of the long arm of chromosome 8: 47,XX, der dup (8)(q13-q22.1).Hypothyroidism can present with delayed fontanel closure.
To establish the extent of disease in an individual diagnosed with cleidocranial dysplasia (CCD), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with cleidocranial dysplasia (CCD), the following evaluations are recommended:Full skeletal survey including the hands and feetAudiologic evaluationDental evaluation by a dentist familiar with CCD and its managementTreatment of ManifestationsEarly referral to a dental clinic familiar with CCD allows for timely planning of necessary procedures. The dental problems that need to be addressed include the retention of deciduous dentition, the presence of supernumerary teeth, and the non-eruption of the permanent dentition. The goal of treatment is to improve appearance and to provide a functioning masticatory mechanism. The goals may be achieved with prosthetic replacements, with or without prior extractions; by removal of the supernumerary teeth followed by surgical repositioning of the permanent teeth; and by a combination of surgical and orthodontic measures for actively erupting and aligning the impacted permanent teeth. For a detailed review, see Becker et al [1997a] and Becker et al [1997b].Speech therapy may be required during periods of dental treatment.Sinus and middle ear infections need aggressive and timely treatment; tympanostomy tubes should be considered when middle ear infections are recurrent [Visosky et al 2003].The fontanels close with time in the majority of individuals and cranial remodeling is usually not necessary; however, if the cranial vault defect is significant, the head should be protected from blunt trauma; helmets may be advised for high-risk activities. In these cases, evaluation by a craniofacial surgeon and rehabilitation services is indicated.If bone density is below normal on DEXA, treatment with calcium and vitamin D supplementation should be considered. Preventive treatment for osteoporosis should be initiated at a young age since peak bone mineral density is achieved in the second and third decade.SurveillanceChildren with CCD should be monitored for the following:Orthopedic complicationsDental abnormalitiesUpper-airway obstruction. Because of the craniofacial involvement, signs and symptoms of obstructive upper-airway disease should be elicited. When symptoms are suggestive, a sleep study is indicated and surgical intervention may be required.Sinus and ear infectionsHearing loss. Regular audiometry in individuals with repeated ear infections allows the identification and early management of hearing loss if it develops.Osteoporosis. DEXA to measure bone mineral density should be done early in adolescence and every five to ten years thereafter. If there are clinical signs of osteopenia (increased number of fractures), evaluation and treatment should be started earlier.Pregnant women with CCD should be monitored closely for cephalopelvic disproportion, which may require delivery by cesarean section.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherIndividuals with CCD should be followed by their primary care physician and receive regular immunizations and anticipatory guidance as recommended.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Cleidocranial Dysplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDRUNX26p21.1Runt-related transcription factor 2RUNX2 homepage - Mendelian genesRUNX2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Cleidocranial Dysplasia (View All in OMIM) View in own window 119600CLEIDOCRANIAL DYSPLASIA; CCD 600211RUNT-RELATED TRANSCRIPTION FACTOR 2; RUNX2Normal allelic variants. Most documented cases of CCD are caused by mutations in the transcription factor RUNX2 (known previously as CBFA1). At the genomic level, RUNX2 contains nine exons that can be alternatively spliced [Geoffroy et al 1998].Pathologic allelic variants. Mutations in RUNX2 include missense, deletion/splice/insertion variants resulting in premature termination and nonsense mutations. The majority of RUNX2 mutations in individuals with classic CCD affect the runt domain and most mutations are predicted to abolish DNA binding [Lee et al 1997, Mundlos et al 1997, Otto et al 2002]. Microdeletion of the gene is an important cause for CCD. (For more information, see Molecular Genetic Testing and Table A. Genes and Databases.)Normal gene product. The protein, runt-related transcription factor 2 (RUNX2) is a transcription factor involved in osteoblast differentiation and skeletal morphogenesis. RUNX2 is essential for the osteoblast differentiation during intramembranous as well as chondrocyte maturation during endochondral ossification [Zheng et al 2005]. The runt-related transcription factor 2 contains an N-terminal stretch of consecutive polyglutamine and polyalanine repeats known as the Q/A domain, a runt domain, and a C-terminal proline/serine/threonine-rich (PST) activation domain. The runt domain is a 128-amino-acid polypeptide motif originally described in the Drosophila runt gene that has the unique ability to independently mediate DNA binding and protein heterodimerization [Zhou et al 1999].Abnormal gene product. Mutations in RUNX2 result in haploinsufficiency for this gene and are associated with classic CCD. There are exceptions, including the 90insC and Thr200Ala mutations, which are associated with mild CCD, isolated dental anomalies, and significant intrafamilial variability. This finding raises the question of whether hypomorphic/neomorphic effects and genetic modifiers alter the clinical expressivity of these mutations.