Cleidocranial Dysplasia: Symptoms, Types, Causes and Treatment

Cleidocranial dysplasia (CCD) is a rare genetic disorder that primarily affects the development of bones and teeth. Despite its rarity, early recognition and effective management of CCD can make a significant difference in the quality of life for affected individuals. This comprehensive article explores the core symptoms, different types, genetic causes, and modern treatment approaches for CCD, synthesizing the latest research and clinical insights.

Symptoms of Cleidocranial Dysplasia

Cleidocranial dysplasia presents with a recognizable set of symptoms, but their severity and combination can vary widely from person to person. Understanding these symptoms is vital for early diagnosis and targeted management, especially since many signs are unique to this condition.

Symptom	Description	Frequency	Source(s)
Clavicular defects	Underdeveloped or absent collarbones; excessive shoulder mobility	~98%	2 4 5 6
Skull anomalies	Open fontanelles, delayed suture closure, Wormian bones	>90%	2 4 5 6
Dental anomalies	Supernumerary teeth, delayed/failed eruption, retention of teeth	>90%	1 4 6 15
Facial features	Frontal bossing, midface hypoplasia, hypertelorism, brachycephaly	>80%	5 6 18
Short stature	Height below average	~70%	5 6
Other skeletal	Flat feet, scoliosis, pubic symphysis diastasis	Variable	5 6 3
Normal intellect	Cognitive function usually unaffected	Nearly all	5 6

Table 1: Key Symptoms

Clavicular and Skeletal Features

One of the hallmark features of CCD is clavicular dysplasia. The collarbones may be partially formed or completely absent, allowing the shoulders to move abnormally close or even touch in front of the chest—a striking and unique physical trait. This is often accompanied by other skeletal manifestations:

• Open fontanelles and sutures: The soft spots on an infant's skull (fontanelles) and the seams between skull bones (sutures) remain open much longer than normal, sometimes even throughout adulthood. Wormian bones—extra bone pieces within skull sutures—are frequently observed 2 4 5 6.
• Short stature: Most individuals fall below average height for their age and sex 5 6.
• Other skeletal changes: These can include abnormal chest shape (narrow thorax), flat feet, scoliosis (curvature of the spine), and delayed ossification of the pubic bones 5 6 3.

Dental Abnormalities

Dental issues are among the most challenging aspects of CCD and often prompt the initial diagnosis:

• Supernumerary teeth: Extra teeth are common and can be seen in more than 90% of cases 1 4 6.
• Delayed or failed eruption: Permanent teeth often fail to erupt on time or at all, while primary (baby) teeth may remain in place longer than normal.
• Multiple impacted teeth: The presence of teeth that are trapped within the jawbone is frequent, contributing to crowding and malocclusion 1 15.
• Retention of primary teeth: Children may retain baby teeth well into adolescence or adulthood, complicating oral function and appearance 1 4 15.

Craniofacial and Other Features

Individuals with CCD often exhibit a characteristic facial appearance:

• Frontal bossing: Prominent forehead.
• Hypertelorism: Widely spaced eyes.
• Midface retrusion/hypoplasia: The middle part of the face appears sunken or underdeveloped.
• Brachycephaly: Short, broad skull.
• Speech and hearing issues: Speech problems and hearing loss may occur due to craniofacial structure and recurrent ear infections 5.

Intellectual and Systemic Findings

Despite these physical challenges, intelligence and cognitive development are typically normal. However, some individuals may experience additional issues such as:

• Obstructive sleep apnea
• Speech delays
• Recurrent ear infections leading to hearing problems 5

Types of Cleidocranial Dysplasia

While cleidocranial dysplasia is primarily recognized as a single disorder, there is growing understanding of its variability. Let's explore how CCD presents differently among patients and what implications this has for diagnosis and care.

Type/Variant	Distinguishing Features	Genetic Profile	Source(s)
Classic CCD	Typical skeletal and dental features	RUNX2 mutations	4 5 7 8
Mild/Partial CCD	Subtle or incomplete symptom expression	In-frame/partial RUNX2 changes	8 11
Severe CCD	More pronounced skeletal/dental anomalies	Missense in Runt domain	8 11
Sporadic cases	No family history, de novo mutations	Often spontaneous mutation	1 7 12
Overlap syndromes	Features mimicking other skeletal dysplasias	RUNX2 variants, rare	3 8

Table 2: Clinical Types and Variants

Classic Cleidocranial Dysplasia

The majority of individuals diagnosed have the "classic" form, which features the full spectrum of symptoms: clavicular hypoplasia or aplasia, open fontanelles, supernumerary and impacted teeth, midface hypoplasia, and short stature. These cases almost always have detectable mutations in the RUNX2 gene 4 5 7 8.

Mild or Partial Expression

Some patients exhibit only a subset of the classic symptoms. For instance, they may have dental anomalies without skeletal involvement, or vice versa. This milder presentation is often associated with specific in-frame mutations or partial loss-of-function changes in RUNX2 8 11.

Severe Phenotypes

Certain mutations, especially missense variants in the RUNX2 Runt domain, are linked to more pronounced forms of CCD, with more severe dental and skeletal anomalies, including macrocephaly, multiple supernumerary teeth, and greater stature reduction 8 11.

Sporadic and Familial Cases

Most CCD cases are inherited in an autosomal dominant pattern, but spontaneous (de novo) mutations can also produce classic CCD in individuals with no family history. Multiple case studies indicate that the proportion of de novo mutations ranges from 5% in familial clusters to over 70% in single-case reports 1 7 12.

Overlap with Other Conditions

Rarely, CCD can mimic or overlap with other skeletal dysplasias, such as hypophosphatasia. These cases may present with additional biochemical abnormalities and atypical clinical features, complicating diagnosis 3 8.

Causes of Cleidocranial Dysplasia

CCD is fundamentally a genetic disorder, with a well-established molecular cause. Understanding the underlying mechanism helps to clarify why the symptoms are so specific.

Cause/Mutation	Molecular Effect	Clinical Impact	Source(s)
RUNX2 gene mutation	Impaired osteoblast differentiation	Skeletal/dental defects	7 8 9 10 12
Haploinsufficiency	Reduced gene dosage/function	Classic CCD phenotype	10 12 11
Missense in Runt domain	Abolish DNA-binding activity	Severe phenotype	8 10 11
Null mutations	Loss of function (nonsense, frameshift)	Variable severity	8 11
In-frame mutations	Partial function loss	Mild to moderate CCD	8 11
De novo mutations	New, spontaneous mutations	Sporadic cases	1 7 12

Table 3: Genetic Causes and Mechanisms

RUNX2 and Bone Development

The main gene responsible for CCD is RUNX2 (also called CBFA1/OSF2/PEBP2alphaA), which encodes a transcription factor crucial for osteoblast differentiation—the cells responsible for bone formation 7 9 10 12. RUNX2 is essential for both membranous and endochondral ossification, explaining why both skull and long bones are affected in CCD 12.

Types of Mutations

• Missense mutations in the Runt domain: These are particularly impactful, abolishing RUNX2's DNA-binding activity. As a result, bone and tooth development are severely disrupted. Patients with these mutations often have more severe symptoms 8 10 11.
• Null mutations (nonsense, frameshift): These lead to truncated, nonfunctional proteins or absence of the protein altogether. The clinical presentation can range from moderate to severe, depending on how much function remains 8 11.
• In-frame insertions/deletions: These may allow partial protein function and are often associated with milder CCD phenotypes 8 11.
• Haploinsufficiency: Having only one functional copy of RUNX2 (instead of two) is enough to produce the classic CCD phenotype, as shown in both human and animal studies 10 12.

Genotype-Phenotype Correlations

Recent research reveals that the severity and range of CCD symptoms correlate with the type and location of the RUNX2 mutation. Missense mutations in the Runt domain tend to cause more severe dental and skeletal issues, while in-frame mutations elsewhere may lead to partial or milder forms 8 11.

Secondary Genetic and Biochemical Effects

Some CCD patients may display features of other conditions, such as hypophosphatasia, due to secondary effects on enzymes like tissue-nonspecific alkaline phosphatase 3. However, these are rare and do not represent the main pathogenesis of CCD.

Treatment of Cleidocranial Dysplasia

There is no cure for CCD, but a multidisciplinary approach can greatly improve function, aesthetics, and quality of life. Treatment strategies are individualized, reflecting the variability in presentation.

Treatment	Purpose/Focus	Typical Candidates	Source(s)
Dental/orthodontic	Manage supernumerary/impacted teeth, occlusion	Nearly all patients	14 15 16 17 18
Surgical intervention	Expose teeth, correct skeletal defects	Moderate/severe cases	14 16 18 5
Orthognathic surgery	Correct midface hypoplasia, improve function	Facial involvement	5 18
Hearing/speech support	Address recurrent infections, speech issues	Symptomatic patients	5
Genetic counseling	Family planning, diagnosis	All families	4 12 18
Prosthetics/implants	Restore function if teeth cannot be preserved	Failed dental tx	18

Table 4: Main Treatment Modalities

Multidisciplinary Care

Effective CCD management requires coordination between craniofacial surgeons, pediatric dentists, orthodontists, ENT specialists, geneticists, and other healthcare professionals 5 18. This ensures all aspects of the disorder—from skeletal abnormalities to dental function and hearing—are addressed.

Dental and Orthodontic Management

• Early intervention: Diagnosis in early childhood allows for strategic planning to minimize the need for prolonged and complex treatments. Supernumerary teeth can often be detected by age 5-7 and addressed before they complicate permanent tooth eruption 15.
• Surgical exposure and extraction: Removing supernumerary and retained primary teeth, sometimes combined with surgical exposure of permanent teeth, facilitates orthodontic movement and eruption 15 16.
• Orthodontic treatment: Braces and other appliances are used to align erupted teeth and close gaps. Early and active management is crucial to reduce treatment duration and improve outcomes 14 16 17.
• Prosthodontic solutions: In cases where teeth cannot be preserved or orthodontic treatments are unsuccessful, dental implants and prosthetics restore function and appearance 18.

Skeletal and Craniofacial Surgery

For patients with significant midface retrusion or other craniofacial deformities, orthognathic (jaw) surgery may be recommended. Cranioplasty can correct skull defects such as frontal bossing or metopic depression 5 18.

Management of Associated Issues

• Hearing and speech: Recurrent ear infections may require ventilation tubes. Speech therapy is indicated for communication delays 5.
• Obstructive sleep apnea: May require adenotonsillectomy or other airway interventions 5.

Individualized and Lifelong Care

Treatment must be tailored to each patient’s needs, age at diagnosis, severity of symptoms, and personal preferences. Lifelong dental and medical follow-up is essential to monitor for new issues and maintain function and aesthetics 18.

Conclusion

Cleidocranial dysplasia is a rare but well-characterized genetic disorder with distinctive skeletal and dental features. Early recognition and a coordinated, multidisciplinary treatment approach can dramatically improve the lives of those affected.

Key takeaways:

• CCD is marked by underdeveloped clavicles, open skull sutures, and extensive dental anomalies 1 2 4 5 6.
• The disorder is caused by mutations in the RUNX2 gene, with the type and location of mutation influencing severity 7 8 9 10 11 12.
• Symptoms vary widely, from mild to severe, and may overlap with other skeletal disorders in rare cases 3 8 11.
• Management is multidisciplinary and individualized, focusing on dental, craniofacial, and supportive interventions 5 14 15 16 17 18.
• Early diagnosis and proactive, coordinated care lead to the best long-term outcomes.

If you or a loved one is affected by CCD, seeking care from a specialized team with experience in rare skeletal disorders is essential. With advancing research and evolving treatment protocols, the outlook for CCD patients continues to improve.