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Review Article Cleidocranial Dysplasia: Clinical and Molecular Genetics

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Review Article Cleidocranial Dysplasia: Clinical and Molecular Genetics J Med Genet 1999;36:177–182 177 Review article Cleidocranial dysplasia: clinical and molecular genetics Stefan Mundlos Abstract Chinese named Arnold, was probably de- Cleidocranial dysplasia (CCD) (MIM scribed by Jackson.6 He was able to trace 356 119600) is an autosomal dominant skeletal members of this family of whom 70 were dysplasia characterised by abnormal aVected with the “Arnold Head”. CCD was clavicles, patent sutures and fontanelles, originally thought to involve only bones of supernumerary teeth, short stature, and a membranous origin. More recent and detailed variety of other skeletal changes. The dis- clinical investigations have shown that CCD is ease gene has been mapped to chromo- a generalised skeletal dysplasia aVecting not some 6p21 within a region containing only the clavicles and the skull but the entire CBFA1, a member of the runt family of skeleton. CCD was therefore considered to be transcription factors. Mutations in the a dysplasia rather than a dysostosis.7 Skeletal CBFA1 gene that presumably lead to syn- abnormalities commonly found include cla- thesis of an inactive gene product were vicular aplasia/hypoplasia, bell shaped thorax, identified in patients with CCD. The func- enlarged calvaria with frontal bossing and open tion of CBFA1 during skeletal develop- fontanelles, Wormian bones, brachydactyly ment was further elucidated by the with hypoplastic distal phalanges, hypoplasia of generation of mutated mice in which the the pelvis with widened symphysis pubis, Cbfa1 gene locus was targeted. Loss of one severe dental anomalies, and short stature. The Cbfa1 allele (+/-) leads to a phenotype very changes suggest that the gene responsible is not similar to human CCD, featuring hypo- only active during early development, as plasia of the clavicles and patent fonta- implied by changes in the shape or number of nelles. Loss of both alleles (-/-) leads to a bones, but is also important during fetal and complete absence of bone owing to a lack postnatal growth. of osteoblast diVerentiation. These studies show that haploinsuYciency of CBFA1 causes the CCD phenotype. CBFA1 con- Clinical and radiological features The clinical and radiological features have trols diVerentiation of precursor cells into 8–12 osteoblasts and is thus essential for mem- been reviewed by several authors. Table 1 branous as well as endochondral bone for- summarises the clinical and radiological find- mation. ings. Typical clinical findings are shown in fig (J Med Genet 1999;36:177–182) 1. Craniofacial growth is aVected in many ways.13 14 Head circumference is usually at the Keywords: cleidocranial dysplasia; CBFA1 upper limit without being macrocephalic. There is a broad forehead with frontal bossing and some degree of hypertelorism. The mid- Heritable diseases of the skeleton are a diverse frontal area is poorly developed and shows a and complex group of genetic disorders. The frontal groove owing to incomplete ossification diVerent clinical manifestations reflect the of the metopic suture. Closure of the anterior basic mechanisms of skeletal development, fontanelle and sagittal and metopic sutures is patterning, bone and cartilage formation, delayed, often for life. In infants, a generalised growth, and homeostasis. The recent identifi- delay in ossification of the skull can be cation of the genetic basis for several skeletal observed and in extreme cases the parietal disorders has yielded significant insights into bones are not present at birth. With increasing these processes.12 Cleidocranial dysplasia age the unossified areas become smaller and (CCD) is a well defined skeletal disorder with true Wormian bones form, particularly around characteristic clinical findings and autosomal the lambdoid suture. Frontal and paranasal dominant inheritance. Reports of clavicular sinuses are frequently absent or reduced in size. defects appeared as early as 1765,3 but Other changes of the skull include small or Scheuthauer4 was probably the first to describe absent nasal bones, segmental calvarial thick- the syndrome accurately. Marie and Sainton5 in ening, underdevelopment of the maxilla, de- Universitätskinderklinik, Langenbeckstrasse 1, 1898 coined the name “dysostose cléido- layed union of the mandibular symphysis, and a 55101 Mainz, Germany crânienne héréditaire” for this condition. One small cranial base with reduced sagittal diam- S Mundlos of the most colourful families, descendants of a eter and a large foramen magnum. The skeletal 178 Mundlos Table 1 Clinical and radiological features of cleidocranial dysplasia As expected, there is often an associated deficiency of the musculature. Clinical Radiological The pelvis is invariably involved and shows Skull characteristic changes (fig 1C). The name Brachycephaly Multiple wormian bones “forme cleido cranio-pelvienne” was proposed Frontal and parietal bossing Segmental calvarial thickening 16 Open sutures and fontanelleles Unossified sutures and patent fontanelles for this deformity by Crouzon and Buttier. Delayed closure of fontanelleles Dysplastic changes in the basiocciput The widened symphysis pubis (distance be- Relative prognathism Hypoplasia of maxilla tween pubic bones) results from a delay in Soft skull in infancy Delayed mineralisation Depressed nasal bridge Calcification of nasal bone delayed or missing ossification during adulthood. Other changes Hypertelorism Hypoplastic sinuses (paranasal, frontal, mastoid) include hypoplasia and anterior rotation of the Thorax and shoulders iliac wings and wide sacroiliac joints. The Ability to bring shoulders together Hypoplastic, aplastic, or discontinuous clavicles Narrow, sloping shoulders Cone shaped thorax femoral epiphyses are large, the femoral necks Respiratory distress at early age Cervical ribs, missing ribs broad, and there is frequently coxa vara. The Increased mobility Hypoplastic scapulae Pelvis and hips dysplastic pelvis often necessitates caesarean Caesarean section Delayed ossification of pubic bone section in the pregnant female. Hypoplasia of iliac wings A relatively constant abnormality is the pres- Widening of sacroiliac joints Large femoral neck, large epiphyses ence of both proximal and distal epiphyses in Spine the second metacarpals and metatarsals lead- Scoliosis Hemivertebrae, posterior wedging ing to excessive growth and length (fig 1D).917 Kyphosis Spondylolysis and spondylolisthesis Spina bifida occulta All other bones of the hands and feet, especially Hands the distal phalanges and the middle phalanges Brachydactyly Short middle phalanges and metacarpals/tarsals III–V of the second and fifth fingers are unusually Tapering of fingers Hypoplastic distal phalanges Nail dysplasia/hypoplasia Accessory epiphyses especially of 2nd metacarpal short. Cone shaped epiphyses and premature Short, broad thumbs Long 2nd metacarpal closure of epiphyseal growth plates are fre- Clinodactyly of 5th finger Cone shaped epiphyses quently observed and lead to shortening of Dentition Normal deciduous dentition other bones. The poorly developed terminal Supernumerary teeth Impacted, supernumerary teeth phalanges give a tapered appearance to the Delayed eruption Crowding, malocclusion digit. The nails are sometimes hypoplastic/ dysplastic or may even be absent. Final height is significantly reduced in changes result in subtle but characteristic facial patients with CCD. Previous investigations features (fig 1A) that include a large, brachy- indicate that birth length is normal but that cephalic head with parietal and marked frontal height drops below or around the 2nd centile bosses separated by a metopic groove, a between the ages of 4 and 8.18 19 In a study by depressed nasal bridge, hypertelorism with Jensen,17 female patients were more aVected possible exophthalmos, and a small maxilla, than male patients. Patients usually have a which gives the face a small, flattened appear- mildly disproportionate short stature with ance with mandibular prognathism. short limbs compared to the trunk, more Many patients with hypoplastic or even apparent in the upper limbs than the lower. absent clavicles have gone through life, even The palate is often highly arched and clefts working as manual labourers, without disability involving the hard and soft palates have been resulting from this defect. Depending on the described. Dental changes occur frequently degree of clavicular hypoplasia, appearance can and are very characteristic of CCD (fig 1E).20 range from a dimple in the skin to sloping, Retention of the deciduous dentition with almost absent shoulders and the ability to vol- delayed eruption of the permanent teeth is a untarily bring the shoulders together. Accord- relatively constant finding. Dental disability ing to our observations and those of others,915 begins in late youth with the progressive a complete absence of the clavicle(s) is rare, morbidity and loss of the deciduous dentition. whereas hypoplasia of the acromial end is com- Many patients remember living “without mon. Other less common forms of clavicular teeth” for some years until the permanent teeth involvement include the occurrence of two eventually erupted. Permanent teeth show a separate fragments, or the absence of the ster- delay of root development and a lessened but nal end with the acromial end present. Bilater- not entirely absent eruptive potential. Surgical ality is the rule but not always the case. The procedures to promote eruption include the extraction of all deciduous teeth and the missing segment may be represented by fibrous removal of bone overlying the crypts of the pseudarthrosis
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