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Cleidocranial Dysplasia

Synonym: Cleidocranial Dysostosis

, MD, MS and , MD, PhD.

Author Information
, MD, MS
Associate Professor of Paediatrics and Genetics, University of Toronto
Associate Staff Physician, The Hospital for Sick Children
Division of Clinical and Metabolic Genetics
Toronto, Canada
, MD, PhD
Robert and Janice McNair Endowed Chair & Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas

Initial Posting: ; Last Update: August 29, 2013.

Summary

Disease characteristics. Cleidocranial dysplasia (referred to as CCD in this review) is a skeletal dysplasia characterized by delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and multiple dental abnormalities. Manifestations may vary among individuals in the same family. The most prominent clinical findings are abnormally large, wide-open fontanels at birth that may remain open throughout life; mid-face retrusion; abnormal dentition, including delayed eruption of secondary dentition, failure to shed the primary teeth, supernumerary teeth with dental crowding, and malocclusion; clavicular hypoplasia resulting in narrow, sloping shoulders that can be apposed at the midline; and hand abnormalities such as brachydactyly, tapering fingers, and short, broad thumbs. Individuals with CCD are shorter than their unaffected sibs and are more likely to have other skeletal/orthopedic problems such as pes planus, genu valgum, and scoliosis. Other medical problems include recurrent sinus infections and other upper-airway complications, recurrent ear infections, high incidence of cesarean section, and mild degree of motor delay in children under age five years.

Diagnosis/testing. Diagnosis of CCD is based on clinical and radiographic findings that include imaging of the cranium, thorax, pelvis, and hands. RUNX2 (CBFA1) is the only gene in which mutations are known to cause CCD. Molecular genetic testing of RUNX2 detects mutations in 60%-70% of individuals with a clinical diagnosis of CCD.

Management. Treatment of manifestations: Dental procedures to address retention of deciduous dentition, presence of supernumerary teeth, and non-eruption of the permanent dentition. Such procedures may include prosthetic replacements, removal of the supernumerary teeth followed by surgical repositioning of the permanent teeth, and a combination of surgical and orthodontic measures for actively erupting and aligning the impacted permanent teeth. Speech therapy may be required during periods of dental treatment. Aggressive treatment of sinus and middle ear infections; tympanostomy tubes are considered for recurrent middle ear infections. If the cranial vault defect is significant, the head needs protection from blunt trauma; helmets may be used for high-risk activities. Surgical cosmesis for depressed forehead or lengthening of hypoplastic clavicles can be considered. If bone density is below normal, treatment with calcium and vitamin D supplementation is considered. Preventive treatment for osteoporosis should be initiated at a young age.

Prevention of secondary complications: Careful planning of anesthetic management due to craniofacial and dental abnormalities. An otolaryngologist should be consulted to assist in securing the airway, and alternative anesthetic approaches, including neuraxial block, should be considered

Surveillance: Children should be monitored for orthopedic complications, dental abnormalities, upper-airway obstruction, sinus and ear infections, and hearing loss. Monitoring for osteoporosis begins in adolescence. Pregnant women with CCD should be monitored for cephalopelvic disproportion.

Agents/circumstances to avoid: Helmets and protective devices should be worn when participating in high-risk activities.

Genetic counseling. Cleidocranial dysplasia is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo mutation is high. Each child of an individual with CCD has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

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.

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 retrusion
  • Abnormal dentition, including delayed eruption of secondary dentition, failure to shed the primary teeth, variable numbers of supernumerary teeth along with dental crowding, and malocclusion
  • Clavicular 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 thumbs
  • Normal intellect in individuals with typical CCD
Figure 1

Figure

Figure 1. Shoulders in an individual with clavicular hypoplasia may be brought to the midline.

The most prominent radiographic findings in CCD:

  • Cranium
    • Wide-open sutures, patent fontanels, presence of wormian bones (small sutural bones)
    • Delayed ossification of the skull
    • Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses
    • Impacted, crowded teeth; supernumerary teeth
  • Thorax (Figure 2)
    • Cone-shaped thorax with narrow upper thoracic diameter
    • Clavicular 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 scapulae
  • Pelvis
    • Delayed ossification of the pubic bone, with wide pubic symphysis
    • Hypoplasia of the iliac wings
    • Widening of the sacroiliac joints
    • Large femoral neck and large epiphyses
  • Hands (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 phalanges
    • Deformed and short middle phalanges of the third, fourth, and fifth digits with cone-shaped epiphyses
  • Other. Osteopenia with evidence of decreased bone mineral density by DEXA in some individuals is a nonspecific finding.
Figure 2

Figure

Figure 2. Chest x-ray demonstrates clavicular hypoplasia.

Figure 3

Figure

Figure 3. Hand x-ray of a male age 2.5 years with cleidocranial dysplasia
a. Note 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...)

Testing

Chromosome analysis. On occasion individuals with CCD have cytogenetically visible complex chromosome rearrangements [Purandare et al 2008].

Molecular Genetic Testing

Gene. To date, RUNX2 (CBFA1) is the only gene in which mutations are 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 testing

Table 1. Summary of Molecular Genetic Testing Used in Cleidocranial Dysplasia

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
RUNX2Sequence analysis Sequence variants 4about 60% 5
Deletion / duplication analysis 6,7Large microdeletions involving RUNX2 and contiguous gene(s) 810% 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Ott et al [2010]

6. 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.

7. 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.

8. Individuals with these deletions may have the CCD phenotype and additional findings including developmental delay.

9. Ott et al [2010]; 10% of individuals with diagnosis of CDD or 26% of those with normal results on sequencing analysis.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • When 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.
  • Sequence analysis, followed by deletion/duplication analysis, can be considered for diagnostic confirmation, particularly if the findings do not meet clinical and radiologic diagnostic criteria.
  • Individuals with atypical features and developmental delay should have chromosomal microarray (CMA) to evaluate for microdeletions or microduplications that involve RUNX2.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Note: CCD can be diagnosed by ultrasound examination in the offspring of an affected parent as early as 14 weeks' gestation. See Prenatal Testing.

Clinical Description

Natural History

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. Cooper et al [2001] recorded the natural history of 90 affected individuals and 56 first- and second-degree relatives. More recently Roberts et al [2013] reviewed their experience with over 100 patients in South Africa.

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 and low bone mineral density [El-Gharbawy et al 2010].

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. Bufalino et al 2012]. 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.

Genotype-Phenotype Correlations

The spectrum of phenotypic variability in CCD ranges from primary dental anomalies to all CCD clinical features plus osteoporosis. There have been some phenotype-genotype correlations established for the dental manifestations; however, no clear correlation has been established between genotype and clavicular involvement [Otto et al 2002, Bufalino et al 2012].

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 or predict a premature termination upstream of or within the runt domain produce classic CCD by abolishing the transactivation activity of the mutant protein with consequent haploinsufficiency. Hypomorphic mutations that only result in partial loss of protein function (c.1171C>T [p.Arg391*], c.598A>G [p.Thr200Ala], and c.90dupC) 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 missense mutations interfere with nuclear accumulation of RUNX2 protein. In addition, a frameshift mutation in codon Pro402 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].

Penetrance

Mutations in RUNX2 have a high penetrance and extreme variability.

Nomenclature

Cleidocranial dysplasia was originally described as dento-osseous dysplasia affecting several individuals in a large pedigree.

The term cleidocranial dysostosis has been used; however, given that RUNX2 has important functions both during skeletal formation and in bone maintenance, the disease is more correctly considered a dysplasia.

Prevalence

CCD is present at a frequency of one in 1,000,000 individuals worldwide. It affects all ethnic groups. Stevenson et al [2012] found the frequency to be 0.12 per 10000 individuals in the Utah (USA) population, suggesting that the frequency may be higher than previously recognized.

Differential Diagnosis

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.

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. This syndrome was shown to be caused by mutations in FIG4 which encodes a phosphoinositide phosphatase [Campeau et al 2013]. 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/Cranium Bifidum.)

Microduplications upstream of MSX2 have been shown to result in a phenocopy of cleidocranial dysplasia [Ott et al 2012].

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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with cleidocranial dysplasia (CCD), the following evaluations are recommended:

  • Full skeletal survey including the hands and feet, if not performed already as part of the initial diagnostic evaluation
  • Audiologic evaluation
  • Dental evaluation by a dentist familiar with CCD and its management
  • Medical genetics consultation

Treatment of Manifestations

Dental. Early 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], and Roberts et al [2013].
  • Generally, an aggressive approach to coordinate multiple oral surgeries for removal of primary dentition and exposure of permanent dentition is recommended, as watchful waiting for spontaneous eruption after initial delay is not effective.

Speech therapy may be required during periods of dental treatment.

Sinus and middle ear infections require aggressive and timely treatment; tympanostomy tubes should be considered when middle ear infections are recurrent [Visosky et al 2003].

Craniofacial. The fontanels close with time in the majority of individuals and cranial remodeling is usually not necessary.

  • 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 are indicated.
  • Affected individuals may consider having correction of the depressed forehead or lengthening of the hypoplastic clavicles for cosmetic reasons. There have been reports of successful surgical interventions in a very small number of affected individuals [Kang et al 2009, Sewell et al 2013].

Skeletal. 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.

Prevention of Secondary Complications

Anesthetic management of those with CCD needs to be carefully planned since affected individuals may present with a large brachycephalic head with mandibular prognathism and maxillary underdevelopment. In addition, the depressed nasal bridge and hypoplastic sinuses disturb nasal breathing. The dental and craniofacial abnormalities result in predictably difficult airway management. If this is anticipated, an otolaryngologist should be consulted to assist in securing the airway, and alternative anesthetic approaches, including neuraxial block, should be considered [Ioscovich et al 2010].

Surveillance

Children with CCD should be monitored for the following:

  • Orthopedic complications
  • Dental abnormalities
  • Upper-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 infections
  • Hearing 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.

Agents/Circumstances to Avoid

To avoid head trauma, helmets and protective devices should be worn when participating in high-risk sports and activities.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with CCD should be monitored closely for cephalopelvic disproportion, which may require delivery by cesarean section.

Therapies Under Investigation

Search 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.

Other

Individuals with CCD should by followed by their primary care physician and receive regular immunizations and anticipatory guidance as recommended.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Cleidocranial dysplasia is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with cleidocranial dysplasia have an affected parent.
  • A proband with cleidocranial dysplasia may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is high.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include careful clinical examination and consideration of craniofacial and skeletal x-rays if there are signs suggestive of dental or bone abnormalities.

Note: (1) Although some individuals diagnosed with cleidocranial dysplasia have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation cannot be detected in the DNA of either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been demonstrated in a family with three affected sibs and an apparently unaffected mother [Pal et al 2007].

Offspring of a proband. Each child of an individual with cleidocranial dysplasia has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Ultrasound examination. CCD can be diagnosed by ultrasound examination in the offspring of an affected parent as early as 14 weeks' gestation. The most consistent features are abnormal clavicles, which are either short (<5th centile for gestational age) or partially or totally absent. Other less specific findings include brachycephalic skull with undermineralization, frontal bossing, and generalized immature ossification [Stewart et al 2000, Hermann et al 2009].

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as cleidocranial dysplasia are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Cleidocranial Dysplasia: Fact Sheet for Patients
  • Children's Craniofacial Association (CCA)
    13140 Coit Road
    Suite 517
    Dallas TX 75240
    Phone: 800-535-3643 (toll-free); 214-570-9099
    Fax: 214-570-8811
    Email: contactCCA@ccakids.com
  • FACES: The National Craniofacial Association
    PO Box 11082
    Chattanooga TN 37401
    Phone: 800-332-2373 (toll-free)
    Email: faces@faces-cranio.org
  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • MAGIC Foundation
    6645 West North Avenue
    Oak Park IL 60302
    Phone: 800-362-4423 (Toll-free Parent Help Line); 708-383-0808
    Fax: 708-383-0899
    Email: info@magicfoundation.org
  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
RUNX26p21​.1Runt-related transcription factor 2RUNX2 homepage - Mendelian genesRUNX2

Data 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)

119600CLEIDOCRANIAL DYSPLASIA; CCD
600211RUNT-RELATED TRANSCRIPTION FACTOR 2; RUNX2

Normal allelic variants. Most documented cases of CCD are caused by mutations in the transcription factor RUNX2 (known previously as CBFA1). At the genomic level, the longest RUNX2 transcript variant (NM_001024630.3) contains nine exons. Transcript variants that encode different protein isoforms [Geoffroy et al 1998] result from the use of alternate promoters as well as alternate splicing [provided by RefSeq, Jul 2008].

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 of CCD. (For more information, see Molecular Genetic Testing and Table A. Genes and Databases.)

Table 2. RUNX2 Pathologic Allelic Variants Discussed in This GeneReview

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.90dupC
(90insC)
p.Ser31Leufs*130NM_001024630​.3
NP_001019801​.3
c.598A>Gp.Thr200Ala
c.1171C>Tp.Arg391*

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

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]. RUNX2 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 the protein and are associated with classic CCD. There are exceptions, including the hypomorphic alleles with partial loss of protein function (c.90dupC and c.598A>G), which are associated with mild CCD, isolated dental anomalies, and significant intrafamilial variability. This finding raises the question of whether hypomorphic/neomorphic effects of the other RUNX2 allele and/or other genetic modifiers alter the clinical expressivity of these mutations.

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Becker A, Lustmann J, Shteyer A. Cleidocranial dysplasia: Part 1--General principles of the orthodontic and surgical treatment modality. Am J Orthod Dentofacial Orthop. 1997a;111:28–33. [PubMed: 9009920]
  2. Becker A, Shteyer A, Bimstein E, Lustmann J. Cleidocranial dysplasia: Part 2--Treatment protocol for the orthodontic and surgical modality. Am J Orthod Dentofacial Orthop. 1997b;111:173–83. [PubMed: 9057617]
  3. Brueton LA, Reeve A, Ellis R, Husband P, Thompson EM, Kingston HM. Apparent cleidocranial dysplasia associated with abnormalities of 8q22 in three individuals. Am J Med Genet. 1992;43:612–8. [PubMed: 1605259]
  4. Bufalino A, Paranaíba LM, Gouvêa AF, Gueiros LA, Martelli-Júnior H, Junior JJ, Lopes MA, Graner E, De Almeida OP, Vargas PA, Coletta RD. Cleidocranial dysplasia: oral features and genetic analysis of 11 patients. Oral Dis. 2012;18:184–90. [PubMed: 22023169]
  5. Campeau PM, Lenk GM, Lu JT, Bae Y, Burrage L, Turnpenny P, Román Corona-Rivera J, Morandi L, Mora M, Reutter H, Vulto-van Silfhout AT, Faivre L, Haan E, Gibbs RA, Meisler MH, Lee BH. Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase. Am J Hum Genet. 2013;92:781–91. [PMC free article: PMC3644641] [PubMed: 23623387]
  6. Cooper SC, Flaitz CM, Johnston DA, Lee B, Hecht JT. A natural history of cleidocranial dysplasia. Am J Med Genet. 2001;104:1–6. [PubMed: 11746020]
  7. El-Gharbawy AH, Peeden JN, Lachman RS, Graham JM, Moore SR, Rimoin DL. Severe cleidocranial dysplasia and hypophosphatasia in a child with microdeletion of the C-terminal region of RUNX2. Am J Med Genet A. 2010;152A:169–74. [PMC free article: PMC2799546] [PubMed: 20014132]
  8. Garcia-Minaur S, Mavrogiannis LA, Rannan-Eliya SV, Hendry MA, Liston WA, Porteous ME, Wilkie AO. Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2. Eur J Hum Genet. 2003;11:892–5. [PubMed: 14571277]
  9. Geoffroy V, Corral DA, Zhou L, Lee B, Karsenty G. Genomic organization, expression of the human CBFA1 gene, and evidence for an alternative splicing event affecting protein function. Mamm Genome. 1998;9:54–7. [PubMed: 9434946]
  10. Golan I, Baumert U, Hrala BP, Mussig D. Dentomaxillofacial variability of cleidocranial dysplasia: clinicoradiological presentation and systematic review. Dentomaxillofac Radiol. 2003;32:347–54. [PubMed: 15070835]
  11. Golan I, Baumert U, Hrala BP, Mussig D. Early craniofacial signs of cleidocranial dysplasia. Int J Paediatr Dent. 2004;14:49–53. [PubMed: 14706028]
  12. Golan I, Preising M, Wagener H, Baumert U, Niederdellmann H, Lorenz B, Mussig D. A novel missense mutation of the CBFA1 gene in a family with cleidocranial dysplasia (CCD) and variable expressivity. J Craniofac Genet Dev Biol. 2000;20:113–20. [PubMed: 11321595]
  13. Goto T, Aramaki M, Yoshihashi H, Nishimura G, Hasegawa Y, Takahashi T, Ishii T, Fukushima Y, Kosaki K. Large fontanels are a shared feature of haploinsufficiency of RUNX2 and its co-activator CBFB. Congenit Anom (Kyoto). 2004;44:225–9. [PubMed: 15566413]
  14. Hermann NV, Hove HD, Jørgensen C, Larsen P, Darvann TA, Kreiborg S, Sundberg K. Prenatal 3D ultrasound diagnostics in cleidocranial dysplasia. Fetal Diagn Ther. 2009;25(1):36–9. [PubMed: 19169035]
  15. Ioscovich A, Barth D, Samueloff A, Grisaru-Granovsky S, Halpern S. Anesthetic management of a patient with cleidocranial dysplasia undergoing various obstetric procedures. Int J Obstet Anesth. 2010;19:106–8. [PubMed: 19945847]
  16. Jackson WP. Osteo-dental dysplasia (cleido-cranial dysostosis); the "Arnold head". Acta Med Scand. 1951;139:292–307. [PubMed: 14818746]
  17. Kang N, Kim SZ, Jung SN. Correction of depressed forehead with BoneSource in cleidocranial dysplasia. J Craniofac Surg. 2009;20:564–6. [PubMed: 19305258]
  18. Lee B, Thirunavukkarasu K, Zhou L, Pastore L, Baldini A, Hecht J, Geoffroy V, Ducy P, Karsenty G. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia. Nat Genet. 1997;16:307–10. [PubMed: 9207800]
  19. McNamara CM, O'Riordan BC, Blake M, Sandy JR. Cleidocranial dysplasia: radiological appearances on dental panoramic radiography. Dentomaxillofac Radiol. 1999;28:89–97. [PubMed: 10522197]
  20. Mendoza-Londono R, Lammer E, Watson R, Harper J, Hatamochi A, Hatamochi-Hayashi S, Napierala D, Hermanns P, Collins S, Roa BB, Hedge MR, Wakui K, Nguyen D, Stockton DW, Lee B. Characterization of a new syndrome that associates craniosynostosis, delayed fontanel closure, parietal foramina, imperforate anus, and skin eruption: CDAGS. Am J Hum Genet. 2005;77:161–8. [PMC free article: PMC1226190] [PubMed: 15924278]
  21. Morava E, Karteszi J, Weisenbach J, Caliebe A, Mundlos S, Mehes K. Cleidocranial dysplasia with decreased bone density and biochemical findings of hypophosphatasia. Eur J Pediatr. 2002;161:619–22. [PubMed: 12424590]
  22. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997;89:773–9. [PubMed: 9182765]
  23. Northup JK, Matalon R, Lockhart LH, Hawkins JC, Velagaleti GV. A complex chromosome rearrangement, der(6)ins(6)(p21.1q25.3q27)inv(6)(p25.3q27), in a child with cleidocranial dysplasia. Eur J Med Genet. 2011;54:e394–8. [PubMed: 21466863]
  24. Ott CE, Hein H, Lohan S, Hoogeboom J, Foulds N, Grünhagen J, Stricker S, Villavicencio-Lorini P, Klopocki E, Mundlos S. Microduplications upstream of MSX2 are associated with a phenocopy of cleidocranial dysplasia. J Med Genet. 2012;49:437–41. [PubMed: 22717651]
  25. Ott CE, Leschik G, Trotier F, Brueton L, Brunner HG, Brussel W, Guillen-Navarro E, Haase C, Kohlhase J, Kotzot D, Lane A, Lee-Kirsch MA, Morlot S, Simon ME, Steichen-Gersdorf E, Tegay DH, Peters H, Mundlos S, Klopocki E. Deletions of the RUNX2 gene are present in about 10% of individuals with cleidocranial dysplasia. Hum Mutat. 2010;31:E1587–93. [PubMed: 20648631]
  26. Otto F, Kanegane H, Mundlos S. Mutations in the RUNX2 gene in patients with cleidocranial dysplasia. Hum Mutat. 2002;19:209–16. [PubMed: 11857736]
  27. Pal T, Napierala D, Becker TA, Loscalzo M, Baldridge D, Lee B, Sutphen R. The presence of germ line mosaicism in cleidocranial dysplasia. Clin Genet. 2007;71:589–91. [PubMed: 17539909]
  28. Purandare SM, Mendoza-Londono R, Yatsenko SA, Napierala D, Scott DA, Sibai T, Casas K, Wilson P, Lee J, Muneer R, Leonard JC, Ramji FG, Lachman R, Li S, Stankiewicz P, Lee B, Mulvihill JJ. De novo three-way chromosome translocation 46,XY,t(4;6;21)(p16;p21.1;q21) in a male with cleidocranial dysplasia. Am J Med Genet A. 2008;146A(4):453–8. [PMC free article: PMC2663417] [PubMed: 18203189]
  29. Quack I, Vonderstrass B, Stock M, Aylsworth AS, Becker A, Brueton L, Lee PJ, Majewski F, Mulliken JB, Suri M, Zenker M, Mundlos S, Otto F. Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia. Am J Hum Genet. 1999;65:1268–78. [PMC free article: PMC1288279] [PubMed: 10521292]
  30. Roberts T, Stephen L, Beighton P. Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115:46–55. [PubMed: 23102800]
  31. Sewell MD, Higgs DS, Lambert SM. Clavicle lengthening by distraction osteogenesis for congenital clavicular hypoplasia: case series and description of technique. J Pediatr Orthop. 2013;33:314–20. [PubMed: 23482270]
  32. Stevenson DA, Carey JC, Byrne JL, Srisukhumbowornchai S, Feldkamp ML. Analysis of skeletal dysplasias in the Utah population. Am J Med Genet A. 2012;158A:1046–54. [PubMed: 22461456]
  33. Stewart PA, Wallerstein R, Moran E, Lee MJ. Early prenatal ultrasound diagnosis of cleidocranial dysplasia. Ultrasound Obstet Gynecol. 2000;15:154–6. [PubMed: 10776001]
  34. Unger S, Mornet E, Mundlos S, Blaser S, Cole DE. Severe cleidocranial dysplasia can mimic hypophosphatasia. Eur J Pediatr. 2002;161:623–6. [PubMed: 12424591]
  35. Visosky AM, Johnson J, Bingea B, Gurney T, Lalwani AK. Otolaryngological manifestations of cleidocranial dysplasia, concentrating on audiological findings. Laryngoscope. 2003;113:1508–14. [PubMed: 12972925]
  36. Yoshida T, Kanegane H, Osato M, Yanagida M, Miyawaki T, Ito Y, Shigesada K. Functional analysis of RUNX2 mutations in Japanese patients with cleidocranial dysplasia demonstrates novel genotype-phenotype correlations. Am J Hum Genet. 2002;71:724–38. [PMC free article: PMC378531] [PubMed: 12196916]
  37. Zheng Q, Sebald E, Zhou G, Chen Y, Wilcox W, Lee B, Krakow D. Dysregulation of chondrogenesis in human cleidocranial dysplasia. Am J Hum Genet. 2005;77:305–12. [PMC free article: PMC1224532] [PubMed: 15952089]
  38. Zhou G, Chen Y, Zhou L, Thirunavukkarasu K, Hecht J, Chitayat D, Gelb BD, Pirinen S, Berry SA, Greenberg CR, Karsenty G, Lee B. CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia. Hum Mol Genet. 1999;8:2311–6. [PubMed: 10545612]

Chapter Notes

Revision History

  • 29 August 2013 (me) Comprehensive update posted live
  • 25 June 2009 (me) Comprehensive update posted live
  • 3 January 2006 (me) Review posted to live Web site
  • 28 June 2005 (rml) Original submission
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