Cleidocranial dysplasia (CCD) spectrum disorder is a skeletal condition that exists on a spectrum, ranging from classic CCD, characterized by a triad of symptoms including delayed closure of cranial sutures, underdeveloped or missing collarbones, and dental abnormalities, to milder forms and even isolated dental issues without other skeletal features. Understanding the diagnosis of CCD is crucial for effective management and care.
Suggestive Findings for Cleidocranial Dysplasia Diagnosis
Diagnosis of CCD spectrum disorder should be considered in individuals presenting with specific clinical and radiographic findings.
Clinical Indicators
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Large, Open Fontanelles at Birth: Infants with CCD often exhibit unusually large and wide-open fontanelles at birth. These may persist throughout life. A wide-open metopic suture can cause the frontal bones to separate, creating a metopic groove. The forehead tends to be broad and flat, and the cranium is brachycephalic.
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Distinct Craniofacial Features: Additional facial characteristics include frontal and parietal bossing, hypertelorism (increased distance between the eyes), midface retrusion, and a depressed nasal bridge.
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Sloping, Narrow Shoulders: Hypoplasia or aplasia of the clavicles can result in narrow, sloping shoulders that can be approximated at the midline (See Figure 1).
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Dental Abnormalities: Irregularities in dentition are common, encompassing delayed eruption of permanent teeth, failure to lose primary teeth, a variable number of extra teeth leading to crowding, and malocclusion.
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Digit Anomalies: Finger and thumb abnormalities can occur, such as brachydactyly (short digits), tapering fingers, and short, broad thumbs.
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Short Stature: Individuals may experience moderate short stature.
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Normal Intellect: Cognitive function is typically unaffected in CCD spectrum disorder.
Radiographic Indicators
Radiographic findings are essential in confirming a suspected diagnosis of Cleidocranial Dysplasia.
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Cranium:
- Wide-open sutures, patent fontanelles, and the presence of Wormian bones.
- Delayed ossification of the skull.
- Poor or absent pneumatization of the paranasal, frontal, and mastoid sinuses.
- Impacted and crowded teeth, along with supernumerary teeth.
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Thorax:
- Cone-shaped thorax with a narrow upper thoracic diameter.
- Clavicular abnormalities, typically bilateral but not always symmetrical, ranging from complete absence to hypoplastic or discontinuous clavicles. The lateral portions of the clavicles are generally more affected than the medial aspects (See Figure 2).
- Hypoplastic scapulae.
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Pelvis:
- Delayed ossification of the pubic bone with a wide pubic symphysis.
- Hypoplasia of the iliac wings.
- Widening of the sacroiliac joints.
- Elongated femoral head with a short femoral neck and elongated epiphyses, presenting a “chef-hat” appearance.
- Coxa vara.
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Hands:
- Pseudoepiphyses of the metacarpal and metatarsal bones, potentially causing an elongated second metacarpal (See Figure 3).
- Hypoplastic distal phalanges.
- Deformed and short middle phalanges of the third, fourth, and fifth digits, featuring cone-shaped epiphyses.
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Other Findings: Osteopenia or osteoporosis, indicated by decreased bone mineral density on DXA scans, can be present. Some individuals may experience multiple fractures.
Establishing a Definitive Cleidocranial Dysplasia Diagnosis
A clinical diagnosis of CCD spectrum disorder is established in a proband exhibiting characteristic clinical and radiographic findings. Alternatively, a molecular diagnosis can be confirmed in a proband with suggestive findings and the identification of a heterozygous pathogenic (or likely pathogenic) variant in the RUNX2 gene through molecular genetic testing.
It’s important to note that according to ACMG/AMP variant interpretation guidelines, “pathogenic variant” and “likely pathogenic variant” are considered clinically synonymous and diagnostic. Conversely, identifying a heterozygous variant of uncertain significance is not sufficient to confirm or rule out a diagnosis of CCD.
Molecular Genetic Testing in Cleidocranial Dysplasia Diagnosis
Molecular genetic testing strategies for CCD diagnosis may involve single-gene testing, multigene panels, and karyotyping.
Table 1. Molecular Genetic Testing for Cleidocranial Dysplasia Spectrum Disorder
| Gene | Method | Proportion of Probands with Pathogenic Variant Detectable by Method |
|---|---|---|
| RUNX2 | Sequence analysis | ~70%-80% |
| Gene-targeted deletion/duplication analysis | ~15% | |
| Karyotype | See footnote | |
| Unknown | NA | ~5%-15% |
Note: The information in Table 1 is for informational purposes and based on current research data.
Methods Explained:
- Sequence analysis: Detects various types of variants, including small intragenic deletions/insertions, missense, nonsense, and splice site variants. However, it typically does not detect exon or whole-gene deletions/duplications.
- Gene-targeted deletion/duplication analysis: Specifically identifies intragenic deletions or duplications, potentially using techniques like quantitative PCR, MLPA, or gene-targeted microarrays.
- Karyotype: While less common, chromosome analysis (karyotype) may be relevant in rare cases, such as individuals with translocations involving the RUNX2 locus.
Clinical Utility of Cleidocranial Dysplasia Diagnosis
Accurate and timely diagnosis of CCD spectrum disorder is paramount for guiding management, treatment, and genetic counseling. Early diagnosis allows for proactive monitoring of potential complications such as dental issues, recurrent infections, and orthopedic concerns. Furthermore, genetic confirmation aids in understanding inheritance patterns and recurrence risks within families.
Differential Diagnosis
While CCD presents with a distinct set of features, other conditions may share overlapping characteristics. Differential diagnosis is crucial to ensure accurate diagnosis. Conditions to consider include Hypophosphatasia, CBFB-related CCD, Chromosome 16q22 deletion syndrome, Pycnodysostosis, Yunis Varon syndrome, Mandibuloacral dysplasia, Parietal foramina with CCD, and MSX2-related CCD with synpolydactyly. Genetic testing and thorough clinical evaluation are key to differentiation.
In conclusion, Cleidocranial Dysplasia Diagnosis relies on a combination of clinical evaluation, radiographic findings, and molecular genetic testing, particularly the analysis of the RUNX2 gene. A comprehensive approach ensures accurate identification of CCD spectrum disorder, facilitating appropriate management and genetic guidance for affected individuals and their families.“`
