Malformations of the cranial bones are among the most prominent symptoms of CCD. Fontanelles close late or not at all, thus leaving soft spots on top of the head. Similarly, the sutures joining the flat bones of the skull close delayedly or remain partially open. At the same time, several facial bones are underdeveloped. An abnormally small upper jaw, for instance, leads to mandibular prognathism. This condition enhances the impression of a protruding forehead and a prominent chin. The bulging skull seems to be in stark contrast with the wide, rather flat face.
Hypoplastic or absent clavicles are another common finding in CCD patients. The latter occurs in about 10% of all CCD cases. These bone anomalies may entail abnormal development of muscles and it is not uncommon to see CCD patients able to move their shoulders in a wide motion range without sensing any discomfort.
Other parts of the axial skeleton may be affected by this genetic disorder, too. In this context, disturbed development of vertebrae, poor posture due to abnormal curvature of the spine as well as syringomyelia have been described . Different developmental defects may be observed in the pelvic region, e.g., in form of coxa vara, coxa valga, delayed growth of specific pelvic bones and a wide symphysis due to delayed closure.
With regards to the limbs, bones and joints are generally underdeveloped, so CCD patients are of rather short stature. Limbs may be abnormally curved, fingers may be shortened .
Besides skeletal findings, CCD patients have a wide variety of dental defects. Supernumerary teeth are common, teeth may not erupt and/or present enamel hypoplasia. Because these teeth are susceptible for numerous dental diseases, the latter may dominate the clinical picture. In some cases, a cleft palate may be detected.
Entire Body System
- Multiple Congenital Anomalies
If RUNX2 testing is not diagnostic and if strong suspicion persists in an individual with features of CCD spectrum disorder who also has multiple congenital anomalies and/or developmental delay, a karyotype may be considered to evaluate for complex chromosome [ncbi.nlm.nih.gov]
- Dysmorphic Face
The patient's family history showed his father and eldest daughter with similar dysmorphic faces, skeletal disorders and proximal upper extremity weakness. [ncbi.nlm.nih.gov]
- Respiratory Distress in Early Infancy
A narrow thorax may lead to respiratory distress in early infancy. ,  Our patient had classical features of this condition. Autosomal dominant inheritance shows wide variability in expression, but usually showing a high penetrance. [jpgmonline.com]
distress in early infancy. ,  A narrow pelvis may necessitate cesarean section in the pregnant female. [indjos.com]
distress in early infancy which may be experienced because of narrow upper thoracic diameter . [jocr.co.in]
Jaw & Teeth
An orthognathic surgery was performed in the maxilla and mandible during the same procedure to correct an existing dentofacial deformity (class III malocclusion). In addition, malar prostheses were used to correct midface deficiency. [ncbi.nlm.nih.gov]
Dental surgery should be considered for unerupted teeth and orthodontics for malocclusion. Speech therapy may be required. Antibiotics are recommended for recurrent infections. [orpha.net]
- Skeletal Dysplasia
- Coxa Vara
Hips 3,7,8 Hip anomalies include coxa vara which is usually bilateral. Coxa vara is defined as any reduction in the normal angle between the femoral neck and shaft. [scielo.org.za]
LeMesurier AB: Developmental coxa vara. J Bone Joint Surg 1948; 30B:595-605. 6. Amstutz HC. Freiberger RH: Coxa vara in children. Clin Orthop 1966: 22:73-92. 7. Weinstein JN. Kuo KN. Millar EA: Congenital coxa vara. A retrospective review. [healio.com]
Coxa vara is treated by corrective femoral osteotomies. If there is brachial plexus irritation with pain and numbness, excision of the clavicular fragments can be performed to decompress it. [en.wikipedia.org]
Other bone abnormalities that have been found in some patients with Cleidocranial dysplasia may be: a wide pelvic joint, delayed growth of the pubic bone, a hip defect in which the thigh bone angles towards the center of the body (coxa vara), failure [web.archive.org]
- Absent Clavicle
Cleidocranial dysplasia (CCD) is a dominantly inherited disease characterized by hypoplastic or absent clavicles, large fontanels, dental dysplasia, and delayed skeletal development. [ncbi.nlm.nih.gov]
clavicles ): may have two separate hypoplastic segments 5 supernumerary ribs hemivertebrae with spondylosis small and high scapulae Pelvis hypoplasia of iliac bones absent/delayed ossification of the pubic bone (pseudo-widening of the symphysis pubis [web.archive.org]
- Joint Dislocation
dislocations, GPAPP type IMPAD1 Sanger Del Dup NGS Chondrodysplasia, Blomstrand type PTH1R Del Dup NGS Chondrodysplasia, Grebe type GDF5 Del Dup NGS Cleft lip, cleft palate and related disorders NGS panel BMP4, COL11A1, COL11A2, COL2A1, COL9A1, COL9A2 [ctgt.net]
According to Cooper et al. in 2001, 57% suffer from flat feet, 28% from knock-knees and 18% from scoliosis, while joint dislocation of the shoulder and elbow may also occur . [pocketdentistry.com]
dislocation at the shoulder and elbow [ El-Gharbawy et al 2010 ]. [ncbi.nlm.nih.gov]
- Coxa Valga
valga), curvature of the spine (scoliosis), a small shoulder blade, and/or curvature of the upper legs so that the knees appear unusually close together (genu valgum). [web.archive.org]
Special images reveal coxa vara and coxa valga. Bones of forearms and lower legs may be shortened or absent. Phalanges are often not fully developed either. [symptoma.com]
Face, Head & Neck
- Delayed Closure of Fontanelles
Cleidocranial dysplasia (CCD) is a rare genetic disorder of bone, characterised by hypoplastic/aplastic clavicles, delayed closure of fontanelles and sutures of the cranium and dental abnormalities. [ncbi.nlm.nih.gov]
Other symptoms can include: Ability to touch shoulders together in front of body Delayed closure of fontanelles ("soft spots") Loose joints Prominent forehead ( frontal bossing ) Short forearms Short fingers There is often a family history of cleidocranial [nlm.nih.gov]
Other symptoms can include: Ability to touch shoulders together in front of body Delayed closure of fontanelles ("soft spots") Loose joints Prominent forehead ( frontal bossing ) Short forearms Short fingers Exams and Tests There is often a family history [nicklauschildrens.org]
In moderate to severe cases, clinical presentation should already raise suspicion for CCD. Due to the disease being a genetic disorder inherited with a dominant trait, familial anamnesis may reveal important information as to the condition of relatives.
Imaging diagnostics are the method of choice to confirm skeletal anomalies and to assess their extent.
Standard radiography and computed tomography frequently reveal large fontanelles, widened skull sutures, particularly visible at the metopic suture, protruding frontal and parietal bones, but a flat face. Interestingly, prevalence of wormian bones is increased in CCD patients. Also, an altered anatomy of ear structures may be encountered and may be related to a medical history of recurrent ear infections or even hearing loss . Supernumerary teeth that often fail to erupt are also visible on radiographic images of the head.
Thoracic images show clavicular hypoplasia or aplasia. It is not uncommon to find two separate hypoplastic clavicle segments . There may be supernumerary ribs and vertebra malformations. Scapulae are sometimes abnormally small. With regards to the pelvis, developmental defects and a wide symphysis pubis may be detected. Special images reveal coxa vara and coxa valga.
Bones of forearms and lower legs may be shortened or absent. Phalanges are often not fully developed either.
If blood samples are analyzed, alkaline phosphatase levels are usually found to be below their physiological range .
There is no causative treatment for the genetic disorder underlying CCD. However, supportive care may be offered as necessary. In this context, orthopedics, otolaryngologists and dentists should be consulted regularly from childhood. Some problems may require surgery to improve the quality of life of the patient, e.g., to correct skull defects and malformations of the hip.
With regards to dental care, deciduous teeth should be maintained as long as possible, if they are not destroyed by caries, because underlying permanent teeth may not necessarily erupt. Supernumerary teeth are often removed. Prolonged orthodontic and possibly prosthodontic treatments may be required to establish a well aligned dental arch.
Most cases of CCD are rather mild and have a good prognosis. Bone malformations rarely cause severe problems, but affected individuals are more prone for ear and upper respiratory tract infections, that may be recurrent and cause long-term sequelae. CCD patients are also more susceptible for dental diseases. Thus, they should pay special attention to dental care.
CCD is a genetic disorder that is inherited with an autosomal dominant trait . The mutated gene triggering osseous and dental malformations is located on chromosome 6, arm p, position 21. It is most frequently denominated RUNX2, but CBFA1 and AML3 are alternative names for the same gene. Various mutations have been identified in that gene that may cause CCD, but as of yet, no relation between genotype and phenotype has been established. RUNX2 gene mutations have a high penetrance, but expression varies widely. Thus, clinical presentation of CCD patients is quite heterogenous.
RUNX2 encodes for the alpha subunit of Runt-related transcription factor 2, member of the RUNX transcription factor family. It plays major roles in osteoblast differentiation, hypertrophy of cartilage at the growth plate and dentin development. Bone formation by intramembranous ossification and tooth development are thus impaired by mutated, defective RUNX2.
Of note, about one out of three CCD patients does not present any RUNX2 mutation. Most likely, they suffer from other genetic disorders, but these have not yet been identified. Because there are rare cases of CCD patients with RUNX2 mutations that display additional gene defects in close proximity to the RUNX2 gene, such genes may serve as a starting point for determining those mutations triggering non-RUNX2 CCD.
The overall prevalence of CCD has been estimated to be 1 per 1,000,000 individuals. Although neither gender nor racial predilection could be proven, prevalence is increased in certain small and isolated groups. Here, spontaneous mutation of RUNX2 persisted within these groups by means of a founder effect.
Of note, expression of RUNX2 mutations varies widely between different CCD patients and a large share of affected individuals suffers only from mild forms of the disease. These may not always be diagnosed and thus, the true prevalence of CCD may be somewhat higher than the aforementioned value suggests.
RUNX2 encodes for the alpha subunit of a transcription factor also known as core-binding factor, which is why the gene is sometimes designated as core-binding factor subunit alpha (CBFA1). The beta subunit of this transcription factor is encoded by another gene which is denominated CBFB. Only the alpha subunit eventually binds to the DNA, notably to enhancers and promoters, but the beta subunit significantly augments its affinity. Of note, mutations in the CBFB gene have not been related to CCD.
RUNX2 may undergo amino acid changes, be shortened due to a premature stop signal in its base sequence or be missing altogether. All these mutations render a defective transcription factor and the expression patterns of several genes regulated by those enhancers or promoters it physiologically binds to are altered in CCD patients. Although homozygous patients dispose of one functional copy of RUNX2, the decrease in RUNX2 overall activity caused by the abnormal version of the gene cannot be completely compensated for.
RUNX2 is particularly active in chondroblasts, osteoblasts, ameloblasts and odontoblasts and therefore affects cartilage, bone, dentin and enamel formation .
Genetic counseling is recommended to families with a known history of CCD.
In general, the chance for a child to inherit the mutated gene is 50% and since the allele is dominant, 50% of all children will develop the disease. Prenatal sonographic examinations may help to detect developmental defects caused by CCD in early to mid gestation. While at 12 weeks of pregnancy characteristic CCD defects might not yet be visible, unmineralized areas of the skull, large fontanelles, delayed development or absence of nasal bones or clavicles may be recognized from week 15 onwards .
Cleidocranial dysplasia (CCD) is a rare genetic disorder also termed cleidocranial dysostosis, mutational dysostosis or Scheuthauer-Marie-Sainton syndrome . Both of the terms dysplasia and dysostosis may be considered correct since in CCD, bone malformation (dysplasia) results from defective ossification (dysostosis). However, syndromes of bone dysplasia usually affect all bones of the body in a similar manner whereas those of dysostosis are generally limited to determined regions or tissues. Today, CCD is the term more commonly used because the disease is understood as a generalized disorder of bone development .
The disease is inherited with an autosomal dominant trait; the gene accounting for CCD has been identified as that encoding for Runt-related transcription factor 2 (RUNX2), which serves as transcription factor during osteoblast and odontoblast differentiation . Thus, patients suffering from CCD show generalized dysplasia of bones and teeth. With regards to osseous malformation, skull and clavicles are most severely affected. These are precisely the bones undergoing intramembranous ossification during development. Here, ossification is delayed, fontanelles close late or not at all, skull sutures remain abnormally wide and clavicles are frequently hypoplastic or absent. CCD patients also present a wide variety of dental malformations. The extent of osseous and dental lesions is diagnosed by means of clinical examination and radiographic imaging.
Cleidocranial dysplasia (CCD) is a rare genetic disorder characterized by generalized skeletal malformations and tooth development defects. CCD may also sometimes be referred to as cleidocranial dysostosis.
CCD is caused by one of several mutations affecting gene RUNX2. This gene encodes for a protein that fulfills regulatory functions in cartilage, bone and tooth development.
Each person inherits two copies of the RUNX2 gene, one from their mother and one from their father. Because the mutated gene is dominant, it is sufficient to inherit one mutated gene in order to develop the disease. Of note, this also means that there is a 50% chance for any child of a CCD patient to inherit the disease. If CCD patients wish to have a child, they should look for genetic counseling.
The most prominent symptoms of CCD concern cranial and facial bones, clavicles and teeth.
Soft spots on top of the head mark unclosed fontanelles and the sutures that join the flat cranial bones may also be widened. Furthermore, the head of a CCD patient is often characterized by a protruding forehead, an abnormally small upper jaw and thus mandibular prognathism. Ear structures may be altered. The face is typically wide and rather flat.
Clavicles may be underdeveloped or completely absent, a feature that confers the ability to move the shoulders towards the front without sensing any discomfort. Other deformations may affect spine, pelvis and limbs.
Diagnosis is based on anamnesis and familial medical history, clinical presentation and radiographic findings. Images of the head, the thorax, spine and pelvis as well as of upper and lower limbs will be obtained to assess the extent of developmental defects. There may be great differences between distinct CCD patients.
Genetic testing may be conducted to confirm the diagnosis, but is usually not necessary if a familial history of CCD is known.
There is no causative treatment for CCD. A multidisciplinary approach is required to treat CCD patients: Orthopedic problems may indicate a surgical intervention and this might also be the case for skull malformations. An otolaryngologist should be consulted if recurrent ear and upper respiratory tract infections occur. An adequate dental hygiene is necessary to protect defective teeth from caries and other diseases. Nevertheless, prolonged dental treatments will probably be required to establish a well aligned, health dental arch.
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