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At a glance

Generalized skeletal dysplasia resulting in defects in the development of skull, clavicles, pelvis, and teeth.

Synonyms

Cleidocranial Dysostosis; Scheuthauer-Marie-Sainton Syndrome; Marie-Sainton Syndrome; Dento-Osseous Dysplasia.

History

The disorder bares the synonymous name of the two French physicians Pierre Marie (1853-1940) and Paul Sainton (1868-1958), who described the disease in 1898 and named it “Dysostose Cléido-Crânienne Héréditaire.” However, the first medical description was most likely by Johann Friedrich Meckel the Elder (1724-1774), who described the disease already in 1760. The Austrian-Hungarian surgeon Gustav Scheuthauer (1832-1894) elaborated on the disease in 1871.

Incidence

The estimated prevalence is in the range of 1:1,000,000. More than 500 cases without ethnic or sexual predilection have been reported worldwide.

Genetic inheritance

Autosomal dominant, but sporadic cases have also been described. There is a wide variability in expression.

Pathophysiology

The disorder is caused by heterozygous duplication with a gain of function in the RUNX2 (Runt-Related Transcription Factor 2, also known as transcription factor CBFA1, Core-Binding Factor Runt Domain, Alpha Subunit 1) gene of the runt domain gene family, which has been mapped to chromosome 6p21.1. RUNX2 controls the differentiation of precursor cells into osteoblasts and is essential for both membranous and endochondral bone formation, but also for hypertrophy of growth plate cartilage, cell migration, and vascular invasion of osseous tissues. RUNX2 has also been referred to as the “master gene” of bone development. The genetic defect results in generalized dysplasia of bone and dental tissue. Initially, it was postulated that the disease affects only the membranous bones (neurocranium, a portion of the clavicle, and some facial bones). However, cleidocranial dysplasia (CCD) is now recognized as a generalized skeletal dysplasia. There is growth retardation and a slight effect on skeletal maturation over time.

Diagnosis

Based on the clinical findings of skull, dental, pelvic, and clavicular malformations and confirmed with genetic mapping. Radiographs show persistently open (or delayed closure of) skull sutures and fontanelle with bulging of the calvarium, short middle phalanx of the fifth finger, and characteristic bone changes.

Clinical aspects

The disease has a highly variable phenotype. It mainly affects the head and neck with brachycephaly, enlarged calvaria, frontal, parietal and occipital bossing with wide forehead, midline depression of the upper forehead, and hypertelorism, flat nasal bridge, wormian bones, large foramen magnum, hypoplasia or absence of frontal and paranasal sinuses, midfacial hypoplasia, micrognathia, nonunion of the mandibular symphysis, high-arched or cleft palate, delayed eruption of deciduous and permanent teeth, enamel and root hypoplasia, cavities, supernumerary teeth (up to 30 extra teeth have been described), and conductive hearing loss. ☞Arnold-Chiari I malformation, syringomyelia, atlantoaxial subluxation with subsequent myelopathy, and crowding of the posterior fossa with tonsillar and uncal ...

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