What is CCD?
Cleidocranial dysplasia (CCD) is a skeletal disorder characterized by open fontanelles (soft spot), small or absent clavicles (collarbones), and multiple dental abnormalities. It is a genetic birth defect caused by mutations to the RUNX2 gene. It occurs one in every one million births. It can be passed from an affected parent or can be a random mutation. Manifestations may vary among individuals in the same family.
Short stature: Average height for men is 5’2”-5’6”. Average height for women is 4”9”-4’10”
HEAD and NECK
Delayed closure of fontanelles (soft spots)
Large, open soft spot at birth that may close or remain open throughout life
Parietal bossing (broad/flat forehead)
Small mid-face: the portion of the face comprising nasal (nose), maxillary (upper jaw), and zygomatic bones (cheekbones) and the soft tissues covering these bones
Frontal bossing: prominent, protruding forehead
Metric groove: vertical dent in the middle of the forehead, normally not present at birth
Micrognathia: small lower jaw
Hypertelorism: increased distance between the eyes
Low nasal bridge
Narrow, high-arched palate (roof of mouth)
Failure to lose baby teeth
Failure for permanent teeth to come in on their own
Supernumerary (extra) teeth
Enamel hypoplasia: thin enamel caused by poor enamel formation
Jaw malocclusion: poor bite
Respiratory distress in early infancy
Narrow thorax (chest)
Ability to touch shoulders together
Small or absent clavicles (collarbones) with sloping shoulders
Cervical ribs: extra ribs that arise from vertebrae in the neck
Osteopenia: reduced bone mass
Increased bone fragility
Wormian bones: extra bone pieces that occur within the joints of the cranium
Bossing (protruberance) of frontal bone
Bossing of occipital bone
Bossing of parietal bone
Calvarial (skull) thickening
Absent or small frontal sinuses
Absent or small paranasal sinuses
Large foramen magnum: the hole at the base of the skull through which the spinal cord passes
Spondylolysis: a defect in the vertebral arch in the lumbar or cervical vertebrae
Spondylolisthesis: a condition where one vertebral body is slipped forward over another
Scoliosis: a lateral curve in the spine
Kyphosis: a curve in the spine that results in a bulge at the upper back
Wide pubic symphysis (the joint in the pubic bone)
Delayed mineralization of pubic bone
Broad head of the femur bone
Short neck of the femur bone
Coxa vara: hip deformity where the head and shaft of the femur is reduced to less than 120 degrees, resulting in a short leg and a limp
Underdeveloped iliac wing (pelvic bone)
Brachydactyly: short fingers
Long second metacarpal (hand bone)
Short middle bones of second and fifth fingers
Cone-shaped finger tips
Short and broad thumbs
Gene valgum: a condition in which knees are deviated towards midline of the body and touch one another when the legs are straightened (“knock knee”)
Lower or flattened arches in the feet
Syringomyelia: fluid-filled cysts in the spinal cord
What are other medical conditions seen in individuals with CCD?
recurrent sinus infections
recurrent ear infections
high incidence of cesarean section
mild degree of motor delay in children under age five years.
Fine-motor skills (grasping a pencil, using a spoon)
Gross-motor skills (walking, hopping, climbing stairs)
How is CCD Diagnosed?
1) Physical exam and clinical findings.
CCD can be diagnosed by they “characteristic triad” of
small or absent clavicles, open fontanelles (soft spot), and supernumerary (extra) teeth
Other clinical findings include small mid-face, abnormal teeth, hand abnormalities, normal intellect
2) X-ray findings:
Skull: wide or open fontanels (soft spot), presence of wormian bones; delayed bone formation; poor development of paranasal, frontal or mastoid sinuses; crowded or extra teeth
Chest: narrow thorax, small or absent clavicles, small scapulae
Pelvis: wide symphysis pubis, small pelvic bones, wide sacroiliac joint, short femoral neck
Hands: long second metacarpal, underdeveloped distal finger bones, cone-shaped finger tips
3) Genetic testing. The test looks for changes in the RUNX2 gene. The gene is found 60-70% of the time in people with a clinical diagnosis of CCD.
Prenatal diagnosis can be made by ultrasound examination in offspring of affected parent as early as 14 weeks.
Other conditions that share characteristics with CCD:
Congenital psyeduoarthrosis of the clavicle
Parietal foramina with cleidocranial dysplasia
Children with CCD should be monitored for the following:
What causes CCD?
Humans have 23 pairs of chromosomes. 22 pairs are called autosomes the 23rd pair, the sex chromosomes, differ between males and females.
Humans have about 20,000 functioning (or protein coding) genes, found on the 23 chromosomes.
Humans have two of each gene, one from mother and one from father. If your parents each give you matching genes, they are called homozygous. If the genes are different from each other, they are called heterozygous.
A mutation is the changing of the structure of a gene.
When one gene has less or no function, it is called a loss-of function mutation.
The gene causing CCD is the RUNX2 gene and is found on the 6th chromosome.
The 6th chromosome has 1,048 protein coding genes, the RUNX2 gene is one of these.
Cleidocranial dysplasia (CCD) is caused by heterozygous loss-of-function mutation in the RUNX2 gene on the 6th chromosome.
The mutation to the one gene can be: 1) passed from an affected parent 2) can be a new or random mutation.
CCD is an autosomal dominant trait. This means the gene affected is on an autosome (one of the 22 pairs of chromosomes that is not the sex chromosome). It only takes a single abnormal gene (not an abnormal chromosome) from either parent to cause an autosomal disorder.A dominant trait means an abnormal gene from one parent can cause the disease. This happens when the matching gene from the other parent is normal. The abnormal gene dominates. A parent with an autosomal dominant conditions has a 50% chance of having a child with the condition. This is true for each pregnancy (Each pregnancy is a 50/50 chance. The child’s risk for the disease does not depend on whether their sibling has the disease).
CHILDREN WHO DO NOT INHERIT THE ABNORMAL GENE WILL NOT DEVELOP THE DISORDER.
CHILDREN WHO DO NOT INHERIT THE ABNORMAL GENE CANNOT PASS ON THE DISORDER.
Timeline & Evolution of CCD
The main clinical features of CCD include persistently open fontanels (soft spots) with bulging skull, underdeveloped or absent of the clavicles (collarbones), wide pubic symphysis (the joint of the pubic bones), short middle phalanx (bone) of the fifth fingers, dental anomalies, and often vertebral (bones of the spinal column) abnormalities.
Link to article: Cleidocranial dysplasia: clinical and molecular genetics by Stefan Mundlos
The evolution of Cleidocrainal dysplasia knowledge/research
|1765||Reports of the defect first appeared|
|1898||Marie and Sainton||Coined dysostose cleidocranienne hereditaire or cleidocranial dysostosis|
|1909||Skeleton of a 25 year-old man showed underdeveloped clavicles, open anterior soft spot, and touching knees (genu valgum).|
|1951||Jackson||356 descendants were traced to the Chinese man Arnold, 70 of whom were affected with the “Arnold Head.” He lived in South Africa and had 7 wives.|
|1976||Arvystas||Reported a family with delayed eruption of baby and permanent teeth, probably CCD|
|1987||Dore et al||Described association of CCD and syringomyelia (fluid-filled cysts in the spinal cord)|
|1987||Silence, et al||Proposed the gene symbol “CCD”
Studied CCD in mice and found the homozygous (2 mutated RUNX2 genes) state in mice was lethal.
|1990||Jensen||Height and radius length are decreased, especially in females. CCD is a generalized skeletal dysplasia.|
|1992||Chitayat et al||Described the range of variability in affected members in 3 generations of family|
|1993||Reed and Houston||Concluded that under formation of the hyoid bone could be added to the delayed process of bone formation that affects the skull, teeth, pelvis, and extremities.|
|1993||Nienhaus et al||Proposed that CCD gene is located on chromosome 6.|
|1995||Mundlos et al||The CCD gene was assigned to chromosome 6 ( 6p21)|
|2001||Cooper et al||Found the following complications that had previously been unrecognized: genu valga (knock-knee), scoliosis, pes planus (flat foot), sinus infections, upper respiratory complications, recurrent middle ear infections and hearing loss. Primary rate of c-sections was increased. Dental abnormalities: extra teeth, failure to lose baby teeth, abnormal jaw alignment.|
|2002||Morava et al||Mutation causes abnormalities due to defective mineralization.|
|2002||Unger et al||Osteopenia, osteoporosis and decreased alkaline phosphatase likely occur in a minority of patients with CCD.|
|2005||Zheng et al||Humans with CCD have altered endochondral bone formation (where process where bones grow in length, where cartilage turns to bone)|
|2005||Baumert et al||Sequenced the RUNX2 gene and identified 12 RUNX2 mutations. They observed mild to full-blown expression of the CCD characteristics, with variability in families.|
|2010||El-Gharbawy et al||RUNX2 appears to play a role in the formation of bone and bone cell differentiation.|