Cleidocranial dysplasia is a generalized skeletal dysplasia affecting not only the clavicles but almost the entire skeletal system. It is characterized by aplasia or hypoplasia of the clav- icles, enlarged calvaria with frontal bossing, multiple Wormian bones, delayed tooth eruption, supernumerary unerupted teeth, distal phalanges with abnormally pointed tufts, hypoplasia of the pelvis, and numerous other abnormalities.
GENETICS/BIRTH DEFECTS
1. Inheritance: autosomal dominant 2. Cause
a. Caused by mutations in CBFA1 (RUNX2) gene result- ing in haploinsufficiency. Types of mutations identi- fied are:
i. Deletion ii. Insertion iii. Missense
iv. Nonsense
b. The gene for cleidocranial dysplasia: called core- binding factor A1 (CBFA1) (a member of the runt family of transcription factors), mapped to 6p21. The alternative gene name is called RUNX2
c. CBFA1 encodes a transcription factor that activates osteoblast differentiation and plays a role in differen- tiation of chondrocytes
3. No significant genotype/phenotype correlations observed
CLINICAL FEATURES
1. Significant intra- and inter-familial variability of pheno- typic expression
2. Abnormal craniofacial growth a. Head
i. A large brachycephalic head
ii. A broad forehead with frontal bossing iii. Delayed closure of the fontanelles and sutures
iv. Poorly developed midfrontal area showing a frontal groove owing to incomplete ossification of the metopic suture
v. Soft skull in infancy b. Face
i. Frontal and parietal bossings, separated by a metopic groove
ii. A depressed nasal bridge
iii. Hypertelorism with possible exophthalmos iv. A small, flattened facial appearance (midface
hypoplasia) with mandibular prognathism v. An anatomic pattern of dentofacial deformity
consistent with the diagnosis of vertical maxil- lary deficiency (short face syndrome, type 2) c. Oral/dental
i. High arched palate
ii. Clefts involving soft and hard palates
iii. Persistence of the deciduous dentition with delayed eruption of the permanent teeth: a rela- tively constant finding
iv. Impaction of supernumerary permanent teeth v. Crowding/malocclusion
vi. Dentigerous cysts 3. Shoulders and thorax
a. Ability to bring shoulders together
b. Dimplings in the skin secondary to mild hypoplasia of the clavicles
c. Sloping, almost absent shoulders secondary to severe hypoplasia or absence of the clavicles
d. Narrow thorax: may lead to respiratory distress dur- ing early infancy
4. Mildly disproportionate short stature with short limbs comparing to the trunk and more apparent in the upper limbs than the lower
5. Spine a. Scoliosis b. Kyphosis 6. Hands
a. Brachydactyly b. Short distal phalanges c. Tapering fingers
d. Nail dysplasia/hypoplasia e. Short, broad thumbs
f. Clinodactyly of the 5th fingers 7. Other abnormalities
a. Hearing loss b. Abnormal gait c. Joint hypermobility d. Muscular hypotonia
8. Cesarean section often required in the pregnant female due to dysplastic pelvis
DIAGNOSTIC INVESTIGATIONS
1. Molecular genetic studies of mutations involving PEBP2 αA/CBFA1
2. Radiographic findings: generalized failure of midline ossification
a. Skull
i. Delayed closure of the anterior fontanelle (open fontanelle) and sagittal and metopic sutures, often for life
ii. Unossified areas of the skull becoming smaller with increasing age
iii. Multiple Wormian bones formation, particularly around the lambdoid suture
iv. Small or absent nasal bones v. Segmental calvarial thickening vi. Underdeveloped maxilla
vii. Delayed union of the mandibular symphysis viii. Platybasia
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ix. Small cranial base x. A large foramen magnum
xi. Hypoplastic sinuses (paranasal, frontal, mastoid) b. Clavicles
i. Absent clavicles: rare
ii. Pseudarthrosis of one or both clavicles iii. Hypoplasia of the acromial end: common
iv. Two separate fragments
v. Absent sternal end with presence of the acromial end
vi. Bilaterality is the rule but not always the case c. Chest
i. Small bell-shaped thoracic cage ii. Short, oblique ribs
iii. Presence of cervical ribs
iv. Scapula often hypoplastic with deficient supraspinatus fossae and acromial facets v. Associated deficiency in musculature d. Pelvis
i. Widened pubis symphysis resulting from delay in ossification during adulthood
ii. Hypoplasia and anterior rotation of the iliac wings
iii. Wide sacroiliac joints
iv. Delayed ossification of the pubic bone v. Large femoral epiphyses
vi. Unusual shape of femoral head reminiscent of a
‘chef’s hat’
vii. Broad femoral necks viii. Frequent coxa vara e. Spine
i. Hemivertebrae ii. Posterior wedging
iii. Spondylolysis and spondylolisthesis iv. Syringomyelia
v. Spina bifida occulta of the cervical, thoracic, or lumbar region
f. Tubular bones
i. Presence of both proximal and distal epiphyses in the second metacarpals and metatarsals lead- ing to excessive growth and length
ii. Frequent cone-shaped epiphyses and premature closure of epiphyseal growth plates leading to shortening of bones
iii. Wide epiphyses
iv. Unusually short distal phalanges and the middle phalanges of the second and fifth fingers v. Poorly developed terminal phalanges giving a
tapered appearance to the digit
vi. Occasional hypoplasia, dysplasia, and aplasia of nails
g. Dentition: impacted, supernumerary teeth
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: not increased unless a parent is affected with the disorder or has germ line mosaicism b. Patient’s offspring: 50%
2. Prenatal diagnosis a. Ultrasonography
i. Hypoplastic clavicles
ii. Less calcified cranium than expected for gesta- tional age
iii. Other skeletal anomalies
b. Direct DNA testing possible for those families with a known mutation in the CBFA1
3. Management
a. Hearing evaluation
b. Evaluate the presence of submucous cleft palate c. Evaluation of obstructive sleep apnea
d. Medical and surgical therapy for upper airway obstruction, recurrent and chronic sinusitis and otitis e. Monitor skeletal and orthopedic complications
f. Early surgical and orthodontic intervention of unerupted permanent teeth to induce eruption g. Orthognathic surgery to correct mid-face hypoplasia
to reduce or correct significant upper respiratory com- plications and malocclusions
h. Surgical and orthodontic management of vertical maxillary deficiency
i. Women with cleidocranial dysplasia at risk for a Cesarean section delivery
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Fig. 1. An infant and a child with cleidocranial dysplasia showing a large brachycephalic skull, frontal bossing, a large anterior fontanel, widely spaced eyes, flat nasal bridge, and easily proximated shoul- ders.
Fig. 2. A child with cleidocranial dysplasia showing prominent fore- head, wide anterior fontanel and cranial sutures, wide eyes, depressed nasal bridge, and easily proximated shoulders. Radiographs show poorly ossified skull, wide fontanels, cone-shaped thorax, and absence of clavicles.
Fig. 3. A girl with cleidocranial dysplasia at different ages showing short stature, frontal bossing, wide cranial sutures, wide set eyes, depressed nasal bridge, and sloping and easily proximated shoulders.
Fig. 4. An adult with cleidocranial dysplasia showing widened cranial sutures, a characteristic face, and sloping and easily proximated shoul- ders. Radiograph showed a cone-shaped thorax with absent clavicles.
Fig. 5. A father and a son with cleidocranial dysplasia showing char- acteristic clinical findings and a dysplastic left clavicle presenting as two separate fragments, illustrated by radiograph.
