Cleidocranial dysplasia: A concise clinical update for child neurologists

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Author: Joaquin A Pena MD

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A neonate presents with large or wide fontanelles and absent clavicles, enabling unusual approximation of the shoulders in front of the chest--a classic red flag for cleidocranial dysplasia (OMIM # 119600). Recognizing the skeletal and dental pattern early aids in dental and craniofacial planning and genetic counseling.

Key clinical features (what to look for)

• Skull and sutures. Delayed closure of fontanelles and persistent open sutures. Bulging of the frontal bones and a relatively large calvarium are common.
• Clavicles. Hypoplastic or absent, leading to hypermobile shoulders; sometimes this is the earliest and most noticeable sign.
• Dentition. Delayed eruption of primary and permanent teeth, multiple supernumerary teeth, and malocclusion; this often results in long-term health problems.
• Stature and other skeletal findings. Short stature, a wide pubic symphysis, a bell-shaped chest in some patients, and various limb or pelvic abnormalities.
• Neurologic or otolaryngology issues. Intelligence is usually normal; however, hearing loss from recurrent otitis media or ossicular anomalies and speech delays related to dental or craniofacial issues may occur.
  These phenotypic features and their relative frequencies are well summarized in major clinical reviews.

Etiology and genetics: the causes of cleidocranial dysplasia

Cleidocranial dysplasia is most often caused by heterozygous loss-of-function variants in the RUNX2 gene, which encodes the core-binding factor alpha-1 (CBFA1), located on chromosome 6p21. It is a key transcription factor essential for osteoblast differentiation and intramembranous ossification. Heterozygous (haploinsufficient) RUNX2 mutations lead to the cleidocranial dysplasia phenotype; complete loss in animal models results in the cessation of bone formation. RUNX2 variants include nonsense, frameshift, splice-site, and missense mutations (often clustered in the conserved Runt domain), as well as copy number changes.

Inheritance is autosomal dominant with about a 50% chance of transmission from an affected parent. However, many affected individuals result from de novo events. Notably, low-level parental mosaicism has been documented and can increase the recurrence risk beyond simple de novo estimates; therefore, targeted parental testing (using sensitive methods) is recommended when a child is found to have a de novo RUNX2 variant. Additionally, 10% to 30% of patients with clinical features consistent with this condition lack a detectable RUNX2 variant through standard testing, indicating possible locus heterogeneity or undetected regulatory or mosaic changes.

Genotype-phenotype insights (practical applications)

Traditional teaching has focused on a limited genotype–phenotype link, but increasing evidence shows that the type and position of variants are important. Missense mutations within the Runt homology domain often have specific functional effects and, in some cases, are associated with more severe craniofacial or shoulder abnormalities. Recent research also links in-frame Runt homology domain variants to other anomalies. However, expressivity can vary greatly--family members with the same variant may exhibit different severity levels. These details help improve prognosis and guide specific functional testing when necessary.

Differential diagnosis of wide fontanelles and clavicular hypoplasia

Although classical cleidocranial dysplasia has a characteristic triad (open fontanelles, clavicular hypoplasia, and dental anomalies), several other more severe or distinct genetic conditions can mimic parts of the phenotype.

Yunis-Varon syndrome (cleidocranial dysostosis, autosomal recessive)*

Cause. Defects in FIG4, VAC14, or related genes.

Features. Features include severe growth restriction, micrognathia, absent thumbs, distal phalangeal aplasia, cardiac anomalies, and profound neurodevelopmental impairment. Often lethal in infancy.

Cleidocranial dysplasia versus Yunis Varon syndrome. Cleidocranial dysplasia à normal intellect, extended survival; Yunis-Varon syndrome à multisystem, often lethal.

*See MedLink Neurology article on Yunis-Varon syndrome.

Pyknodysostosis

Cause. Biallelic CTSK mutations.

Features. Short stature, osteosclerosis, brittle bones prone to fractures, and a hypoplastic mandible.

Key distinction. Diffuse osteosclerosis + fracture risk (absent in cleidocranial dysplasia).

Hypophosphatasia

Cause. ALPL gene mutations

Features. Wide fontanelles, rachitic changes, premature tooth loss, and low alkaline phosphatase.

Key distinction. Biochemical hallmark (low alkaline phosphatase).

Mandibuloacral dysplasia

Features. Delayed suture closure and clavicular anomalies, along with cutaneous, vascular, or progeroid characteristics.

Clinical tip. Normal cognition combined with multiple supernumerary teeth and isolated skeletal anomalies suggests cleidocranial dysplasia. Severe multisystem involvement or metabolic abnormalities point to alternative diagnoses.

Diagnostic approach

1. Clinical radiology. Skull x-rays or CT scans (patent sutures and fontanelles), clavicle x-rays, and dental panoramic imaging.
2. Genetic testing. Sequence RUNX2, including coding and splice sites, and evaluate for copy-number variants such as exon deletions or duplications. If the results are negative and clinical suspicion remains high, consider exome sequencing, targeted deep sequencing for mosaicism, or testing of regulatory regions in research settings. Due to the risk of recurrence from mosaic parents, consider parental sensitive testing if a variant in the child appears de novo.

Management: multidisciplinary and forward-looking

• Dental and orthodontic. Early intervention (pediatric dentistry, orthodontics, oral or maxillofacial surgery). Extraction of retained deciduous or supernumerary teeth, guided eruption, and prosthodontic work are often planned over several years. Timing influences functional and psychosocial outcomes.
• Orthopedics and craniofacial surgery. Address symptomatic cranial vault or suture issues, shoulder deformities, or pelvic and hip problems if they occur. Most cases of clavicular hypoplasia do not require reconstruction unless they cause functional problems.
• Otolaryngology and audiology. Monitor for conductive hearing loss; intervene as needed.
• Developmental and psychosocial. Monitor speech due to dental issues, provide early therapies as needed, and support psychosocial adjustment.
• Genetic counseling. Explain autosomal dominant inheritance, variable expressivity, recurrence risk, and implications for family planning, including prenatal or preimplantation options when a pathogenic RUNX2 variant is identified. Discuss parental mosaicism and investigate if suspected.

Advances and future research directions

• Enhanced molecular diagnostics. Next-generation sequencing, copy-number detection, and more sensitive assays for mosaicism have increased diagnostic success and improved recurrence-risk predictions. Recent cohort studies have broadened the list of pathogenic RUNX2 variants and started to identify location-specific phenotypic patterns.
• Biology of RUNX2. Ongoing research is clarifying RUNX2’s specific roles in osteoblast differentiation and cranial base development; these findings could eventually lead to targeted bone growth or regenerative therapies. However, there is currently no disease-modifying molecular treatment available for cleidocranial dysplasia; management remains supportive and surgical.
• Precise counseling. Identifying parental mosaicism and the possibility of noncoding or structural causes in RUNX2-negative cases results in more sensitive testing protocols and family-focused counseling.

Practical takeaways for the child neurologist

• When you notice wide fontanelles or abnormal shoulder mobility, consider cleidocranial dysplasia in the differential diagnosis and order specific skeletal imaging and a dental assessment. Early detection enables faster interventions in dental and otolaryngology, which can significantly improve quality of life.
• Facilitate genetic testing, including RUNX2 sequencing and CNV analysis, and involve genetics early for counseling; if testing is negative but suspicion remains, consider extended testing for mosaicism or research options.

Perspective and conclusions

Cleidocranial dysplasia is a well-known autosomal-dominant skeletal disorder, and recognizing key signs, such as large fontanelles, clavicular hypoplasia, and dental abnormalities, aids in targeted genetic diagnosis and comprehensive care. Advances in sequencing and understanding mosaicism have enhanced diagnostic accuracy and counseling, and research on RUNX2 biology has expanded our knowledge of craniofacial and skeletal development. For child neurologists, the main benefit is early detection and referral; timely interventions in dental, otolaryngology, and genetic care can greatly improve function and psychosocial outcomes.

Bibliography

Machol K, Mendoza-Londono R, Lee B. Cleidocranial dysplasia spectrum disorder. GeneReviews Updated 2023, April 13.

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Bharti K, Goswami M. Cleidocranial dysplasia: a report of two cases with brief review. Intractable Rare Dis Res 2016;5:117-20. PMID 27195196

Thaweesapphithak S, Termteerapornpimol K, Wongsirisuwan S, Chantarangsu S, Porntaveetus T. The impact of RUNX2 gene variants on cleidocranial dysplasia genotype: a systematic review. J Trans Med 2024 22(1):1099. PMID 39627759

Muurinen M, Taylan F, Tournis S, et al. Mosaic deletions of known genes explain skeletal dysplasias with high and low bone mass JBMR Plus 2022;6(8):e10660. PMID 35991531

Komori T. Regulation of proliferation, differentiation, and functions of osteoblasts by Runx2. Int J Mol Sci 2019;2 0(7):1694. PMID 30987410

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