Cleidocranial Dysplasia Spectrum Disorder

Clinical characteristics.

Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia that represents a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities) to mild CCD to isolated dental anomalies without the skeletal features. Most individuals come to diagnosis because they have classic features. At birth, affected individuals typically have abnormally large, wide-open fontanelles that may remain open throughout life. Clavicular hypoplasia can result in narrow, sloping shoulders that can be opposed at the midline. Moderate short stature may be observed, with most affected individuals being shorter than their unaffected sibs. Dental anomalies may include supernumerary teeth, eruption failure of the permanent teeth, and presence of the second permanent molar with the primary dentition. Individuals with CCD spectrum disorder are at increased risk of developing recurrent sinus infections, recurrent ear infections leading to conductive hearing loss, and upper-airway obstruction. Intelligence is typically normal.

Diagnosis/testing.

Diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or by the identification of a heterozygous pathogenic variant in RUNX2 (CBFA1).

Management.

Treatment of manifestations: 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. 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; consideration of tympanostomy tubes for recurrent middle ear infections.

Prevention of primary manifestations: Preventive treatment for osteoporosis should be initiated at a young age. Early screening for low bone mineral density and appropriate supplementation with vitamin D and calcium are recommended.

Prevention of secondary complications: Careful planning of anesthetic management due to craniofacial and dental abnormalities. Consultation with an otolaryngologist to assist in securing the airway. Consideration of alternative anesthetic approaches, including neuraxial block, taking into account possible spine abnormalities.

Surveillance: Monitoring of children for orthopedic complications, dental abnormalities, upper-airway obstruction, sinus and ear infections, and hearing loss. Monitoring for osteoporosis beginning in early adolescence and every five to ten years thereafter.

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

Pregnancy management: Monitoring of affected women during pregnancy for cephalopelvic disproportion.

Genetic counseling.

Cleidocranial dysplasia spectrum disorder is inherited in an autosomal dominant manner. The proportion of cases caused by a de novo RUNX2 pathogenic variant is high. Each child of an individual with CCD spectrum disorder has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

Cleidocranial dysplasia (CCD) spectrum disorder should be suspected in individuals with the following clinical and radiographic findings.

Clinical findings

• Abnormally large, wide-open fontanelles 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.
• Frontal and parietal bossing and mid-face retrusion
• Narrow, sloping shoulders that can be opposed at the midline due to clavicular hypoplasia or aplasia (see Figure 1)
• 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
• Hand abnormalities including brachydactyly, tapering fingers, and short, broad thumbs
• Short stature (typically moderate)
• Normal intellect in individuals with classic CCD spectrum disorder

Figure 1.

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

Radiographic findings

• Cranium
  • Wide-open sutures, patent fontanelles, 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
  • Typically bilateral (but not necessarily symmetric) clavicular abnormalities ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions are more affected than the medial aspects of the clavicles (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
  • Elongated femoral head with short femoral neck and elongated epiphyses ("chef-hat" appearance)
  • Coxa vara
• 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/osteoporosis with evidence of decreased bone mineral density by DXA; some affected individuals sustain multiple fractures.

Figure 2.

Chest x-ray demonstrates clavicular hypoplasia.

Figure 3.

Hand x-ray of a male age 2.5 years with cleidocranial dysplasia spectrum disorder 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.

Establishing the Diagnosis

The diagnosis of a CCD spectrum disorder is established in a proband with EITHER of the following:

• The above clinical and radiographic findings of classic CCD
• Suggestive clinical findings and a heterozygous pathogenic variant in RUNX2 (CBFA1) identified by molecular genetic testing (see Table 1)

Molecular testing approaches can include single-gene testing, karyotype, or use of a multigene panel:

• Single-gene testing. Sequence analysis of RUNX2 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  Note: Gene-targeted methods will detect deletions ranging from a single exon to whole genes; however, breakpoints of large deletions and/or deletion of adjacent genes may not be determined.
• Karyotype. If RUNX2 testing is not diagnostic and if strong suspicion persists in an individual with features of CCD spectrum disorder who also has multiple congenital anomalies and/or developmental delay, a karyotype may be considered to evaluate for complex chromosome rearrangements or translocations that involve 6p21.1 (RUNX2 locus) but do not result in RUNX2 copy number changes [Purandare et al 2008, Northup et al 2011].
• A multigene panel that includes RUNX2 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal dysplasia representing a clinical continuum ranging from classic CCD (triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities) to mild CCD to isolated dental anomalies without the skeletal features [Golan et al 2000]. Most individuals come to diagnosis because they have classic features. CCD spectrum disorder 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. Cooper et al [2001] recorded the natural history of 90 probands and 56 first- and second-degree relatives; findings highlight the clinical variability of this condition within affected members of the same family who harbor the same pathogenic variant. Roberts et al [2013] reviewed their experience with more than 100 affected individuals in South Africa. Males and females are affected equally.

Classic CCD. The most prominent clinical findings in individuals with classic CCD are listed in Suggestive Findings and include: abnormally large, wide-open fontanelles at birth that may remain open throughout life; clavicular hypoplasia resulting in narrow, sloping shoulders that can be opposed at the midline; and abnormal dentition (see Dental complications).

Further medical problems identified in individuals with CCD spectrum disorder include the following:

Height. Individuals with CCD spectrum disorder are often 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. Affected individuals 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]
• Osteoporosis, found in 8/14 (57.1%) affected individuals; and osteopenia, identified in 3/14 (21.4%) individuals with CCD spectrum disorder [Dinçsoy Bir et al 2017]

Other less common orthopedic problems include joint dislocation at the shoulder and elbow [El-Gharbawy et al 2010].

Dental complications. Up to 94% of persons with CCD spectrum disorder 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 a CCD spectrum disorder 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 a CCD spectrum disorder are more likely to have an underbite and to have cysts in their gums that usually form around extra teeth [McNamara et al 1999].

ENT complications. Recurrent sinus infections and other upper-airway complications are observed significantly more often in individuals with CCD spectrum disorder than in the general population. When symptoms are suggestive of upper-airway obstruction, a sleep study is indicated and surgical intervention may be required. Conductive hearing loss occurs in 39% of affected individuals. Individuals with CCD spectrum disorder of any age are more likely to have recurrent ear infections.

Endocrinology. Individuals with CCD spectrum disorder can have low IGF-1 levels. Low vitamin D with no consistent association with osteoporosis has also been reported [Dinçsoy Bir et al 2017]. Rarely, individuals with CCD spectrum disorder have low levels of alkaline phosphatase [Morava et al 2002, Unger et al 2002, El-Gharbawy et al 2010].

Development. Intelligence is typically normal. Children younger than 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 genu valgum. No significant differences are observed among elementary school-age children.

Genotype-Phenotype Correlations

Some genotype-phenotype correlations have been established for the dental manifestations. No clear correlation has been established between genotype and clavicular involvement [Otto et al 2002, Bufalino et al 2012, Jaruga et al 2016].

• Heterozygous RUNX2 pathogenic variants located in the runt domain (or predicting a premature termination upstream of or within the runt domain) that abolish the transactivation activity of the mutated protein with consequent haploinsufficiency result in classic CCD.
• Short stature and dental anomalies were found to be milder in individuals with a classic CCD phenotype who had an intact runt domain and higher residual RUNX2 activity when compared to individuals with a classic CCD phenotype in whom the pathogenic variant affected the runt domain [Yoshida et al 2002].
• A clinical spectrum ranging from isolated dental anomalies without the skeletal features of CCD to mild CCD to classic CCD results from hypomorphic pathogenic variants that result in partial loss of protein function (c.1171C>T [p.Arg391Ter], c.598A>G [p.Thr200Ala], and c.90dupC) (see Molecular Genetics). Intrafamilial variability is significant [Zhou et al 1999].
• Osteoporosis leading to recurrent bone fractures and scoliosis has been associated with a heterozygous pathogenic frameshift variant c.1205dupC, reflecting the role of RUNX2 protein in the maintenance of adult bone [Quack et al 1999].

Penetrance

Pathogenic variants in RUNX2 have a high penetrance and extreme variability.

Nomenclature

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

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

Prevalence

CCD spectrum disorder 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 10,000 individuals in the Utah (USA) population, suggesting that the frequency may be higher than previously recognized.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with cleidocranial dysplasia (CCD) spectrum disorder, the following evaluations are recommended if they have not already been completed:

• Full skeletal survey including the hands and feet
• DXA scan for those in early adolescence and older
• Dental evaluation by a dentist familiar with CCD and its management
• Audiologic evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Craniofacial. The fontanelles 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 DXA, treatment with calcium and vitamin D supplementation should be considered.

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], Becker et al [1997b], and Roberts et al [2013].
• Generally, an aggressive approach to coordination of 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.

Upper airway obstruction. When symptoms are suggestive, a sleep study is indicated and surgical intervention may be required.

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].

Endocrinology. The effectiveness of growth hormone (GH) therapy for short stature in this condition has not been proven. Possible adverse effects of GH therapy on the primary chondrodysplastic growth plate are theoretically possible, as RUNX2 is directly involved in chondrocyte differentiation and growth plate maintenance [Zheng et al. 2005].

Prevention of Primary Complications

Preventive treatment for osteoporosis should be initiated at a young age since peak bone mineral density is achieved in the second and third decade. Early screening for low bone mineral density and appropriate supplementation with vitamin D and calcium are recommended.

Prevention of Secondary Complications

Anesthetic management of those with CCD spectrum disorder 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. Alternative anesthetic approaches, including neuraxial block, should be considered, taking into account possible spine abnormalities [Ioscovich et al 2010].

Surveillance

Children with CCD spectrum disorder should be monitored for the following:

• Orthopedic complications
• Dental abnormalities
• Signs and symptoms of upper-airway obstruction
• 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. DXA 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 (i.e., increased number of fractures), evaluation and treatment should be started earlier.

All affected individuals should by followed by their primary care physician and receive regular immunizations and anticipatory guidance as recommended.

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 spectrum disorder should be monitored closely for cephalopelvic disproportion, which may require delivery by cesarean section. The primary cesarean section rate among women with a CCD spectrum disorder is 69%, which is higher than in controls [Cooper et al 2001].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.