Cleidocranial dysplasia (ORPHA:1452)
Cleidocranial dysplasia (CCD) is a rare genetic developmental abnormality of bone characterized by hypoplastic or aplastic clavicles, persistence of wide-open fontanels and sutures and multiple dental abnormalities.
Epidemiology
The prevalence of CCD is 1/1,000,000, with higher rates in groups with a founder effect. The disorder is found in many ethnic groups and no sex predilection has been reported. It may be underdiagnosed because of the number of relatively mild cases.
Clinical description
There is an extremely wide range of clinical manifestations (even within the same family) from isolated dental anomalies to severe malformations with functional repercussions. The main clinical signs are hypoplasia or aplasia of the clavicles with narrow, sloping shoulders that can be approximated anteriorly, delayed fusion of cranial sutures with large, wide-open fontanels at birth that may persist throughout life, and a wide spectrum of dental anomalies including abnormal dentition, uniform or chaotic supernumerary teeth (hyperdontia) in the primary and secondary dentition resulting in crowding and malocclusion, retention of deciduous teeth, delayed eruption of secondary dentition and failure to shed the primary teeth. The dental manifestations may affect articulation and mastication. Other signs include broad flat forehead, hypertelorism, midface hypoplasia, and a pointed jaw giving a characteristic facial appearance as well as brachydactyly, tapering fingers and short, broad thumbs. Associated skeletal abnormalities include short stature, scoliosis, genu valgum, pes planus, a wide pubic symphysis, dysplastic scapulae, and coxa vara, generally with little clinical significance. Secondary complications include recurrent infections of the upper respiratory tract, sleep apnea, mild motor delay and variable degrees of hearing loss. Cognitive and intellectual functions are normal. The proportion of women with CCD requiring cesarean section is higher than in the general population due to cephalopelvic disproportion.
Etiology
CCD is caused by mutations in the RUNX2 gene (6p21) involved in differentiation of osteoblasts and bone formation. A wide range of mutations have been identified, with high penetrance and significant variability. No clear phenotype-genotype correlations have been established.
Diagnostic methods
Diagnosis is based on clinical signs and on characteristic radiographic findings (wide-open sutures, patent fontanels, cone-shaped thorax with narrow upper thoracic diameter, hand deformities, abnormal dentition). Molecular genetic testing can be used to confirm the diagnosis in patients with atypical clinical and radiological diagnostic features.
Differential diagnosis
Differential diagnoses include mandibuloacral dysplasia, Crane-Heise syndrome, Yunis-Varon syndrome, pycnodysostosis, CDAGS syndrome, and hypophosphatasia.
Antenatal diagnosis
Prenatal diagnosis for pregnancies at increased risk is possible and requires identification of the disease-causing genetic mutation in the family.
Genetic counseling
Cleidocranial dysplasia follows an autosomal dominant pattern of inheritance. Genetic counseling should be provided to affected families. The number of cases related to de novo mutations appears to be high.
Management and treatment
Management of dental anomalies is very important with the aim of achieving optimal function and esthetics. Options include removal of retained deciduous, supernumerary and abnormal permanent teeth. Dental surgery should be considered for unerupted teeth and orthodontics for malocclusion. Speech therapy may be required. Antibiotics are recommended for recurrent infections. Because of the role of RUNX2 in bone maintenance and ossification, bone mineral density should be monitored and preventive treatment for osteoporosis considered.
Prognosis
The malformations and complications of CCD rarely cause significant disability. The prognosis is generally good.

                            Last update: 
                            November 2013


                            - Expert reviewer(s): 
                            Dr Roberto MENDOZA-LONDONO