Cleidocranial dysplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and Keywords: Cleidocranial digital dysostosis; Cleidocranial dysplasia; Craniocleidodysostosis; Dysostosis cleidocranialis; Dysostosis cleidocraniodigitalis; Dysostosis cleidocraniopelvina; Dysostosis generalisata; Dysplasia cleidocranialis; Dysplasia cleidofacialis; Marie-Sainton syndrome; Mutational dysostosis; Osteodental dysplasia; Pelvicocleidocranial dysostosis; Scheuthauer-Marie-Sainton syndrome

Overview

Cleidocranial dysplasia, also called Cleidocranial dysostosis, is a hereditary congenital disorder characterized by clavicular hypoplasia oragenesis, narrowed thorax that allows approximation the shoulders in front of the chest, delayed closure of the cranial sutures and fontanelles, Wormian bones, short stature, delayed eruption of secondary teeth, and other skeletal abnormalities. The fontanelles may remain open until adulthood, but the sutures often close with interposition of Wormian bones. Bosses of the frontal, parietal, and occipital regions give the skull a large globular shape with small face. The characteristic skull abnormalities are sometimes referred to as the "Arnold head" named after the descendants of a Chinese who settled in South Africa and changed his name to Arnold. More than 100 additional anomalies may be associated, including wide pubic symphysis, dental abnormalities, short middle phalanges of the fifth fingers, delayed skeletal maturation, hearing deficiency, and mild mental retardation in some cases.[1] It was originally found to involve only bones of membranous origin. However, more recent clinical studies suggest that it is a generalized skeletal disorder that affects the entire skeleton and is therefore considered to be a dysplasia rather than a dysostosis.[2]

Etiopathogenesis

Cleidocranial dysplasia is usually inherited as autosomal dominant, but other modes of inheritance have been reported.[3][4][5][6] Its phenotype is caused by haploinsufficiency of the transcriptional factorRUNX2 (formerly known as CBFA1), which is located on the short arm of chromosome 6 (6p21) and regulates osteoblast differentiation.[7][8]

RUNX2 (runt-related transcription factor 2) gene is a member of the RUNX family of transcription factors and encodes a nuclear protein with a Runt DNA-binding domain. This protein is essential for osteoblastic differentiation and skeletal morphogenesis and acts as a scaffold for nucleic acids and regulatory factors involved in skeletal gene expression. The protein can bind DNA both as a monomer or, with more affinity, as a subunit of a heterodimeric complex. Loss-of-function mutations in this gene affect chondrocyte cell activity and osteoblastogenesid and results in delayed ossification of midline structures of the body, particularly membranous bone. Transcript variants that encode different protein isoforms result from the use of alternate promoters as well as alternative splicing.[9]

Clinical features

Cleidocranial dysplasia is a generalized skeletal condition so named from the collarbone (cleido-) and cranium deformities which people with it often have.[10] Patient usually presents with a painless swelling in the area of the clavicles at 2 to 3 years of age.[11] Common features include:

  • Head and neck: Brachycephaly with bossing of the frontal, parietal, and occipital bossing give the head a large globular appearance with a small face due to hypoplasia of the maxillary and zygomatic bones and relative prognathism.[12] Additional abnormalities include open fontanels; open cranial sutures; calvarial thickening in the supraorbital part of the bone, squama of the temporal bones, and the occipital bone; Wormian bones filling suture lines, occasional absence of the parietal bones, faulty development of the foramen magnum, and dysplasia of the paranasal sinuses and mastoids.
  • Eyes: Hypertelorism.
  • Nose: Broad nose with depressed bridge.
  • Mouth and oral structures: Highly arched palate, cleft palate, delayed union of the mandibular symphysis, failure of eruption of permanent teeth, dental root and crown abnormalities, crypt formation around impacted teeth, and ectopic teeth. Cement formation is also deficient.[13]
  • Neck: Long neck.
  • Thorax: Narrow chest with drooping shoulders. Clavicles can be partly missing leaving only medial part of bone. In 10% cases, they are completely missing.[8] If the collarbones are completely missing or reduced to small vestiges, this allows hypermobility of the shoulders including ability to touch the shoulders together in front of the chest.[12] The defect is bilateral 80% of the time.[14] Partial collarbones may cause nerve damage symptoms and so have to be removed by surgery.
  • Pelvis: Delayed ossification of bones forming symphysis pubis, producing a widened symphysis.
  • Hand and foot: Pseudoepiphyses at the base of the metacarpal bones, abnormal phalangeal tufts of the hands and feet, short middle phalanges of the fifth fingers, and cone-shaped epiphyses of the distal phalanges.[15]
  • Extremities: Coxa vara, coxa valga, and notching capital femoral epiphysis.
  • Spine: Spina bifida, syringomyelia, spondylolysis, and scoliosis have been described.[8]
  • Respiratory system: Occasional respiratory distress
  • Growth and development: Retarded growth with delayed bone maturation and mental retardation in some cases. Bones and joints are underdeveloped. People are shorter and their frames are smaller than their siblings who do not have the condition.
    File:Cleidocranial dysplasia teeth.jpg
    Panoramic view of the jaws showing multiple unerupted supernumerary teeth mimicking premolar, missing gonial angles and underdeveloped maxillary sinuses in cleidocranial dysplasia.
  • Behavior and performance: Conduction deafness.

Diagnosis

File:Cleidocranial2.jpg
Lateral skull radiograph showing open skull sutures, large fontanelles, multiple Wormian bones and underdeveloped paranasal sinuses.

Clinically, different features of the dysostosis are significant. Radiological imaging helps confirm the diagnosis. During gestation, clavicular size can be calculated using available nomograms. Wormian bones can sometimes be observed in skull.[16]

It has one or more of these features:

The following are the imaging findings

  • Poorly ossified skull, widening of the sutures and multiple Wormian bones. In some patients the foramen magnum is deformed, and basilar invagination is often evident.
  • Absence of the clavicles (either partial or total) may be observed.
  • Other findings include:
    • Hypoplastic scapula.
    • Bell-shaped thorax.
    • Pelvic changes including delayed ossification of the pubic bones, a wide symphysis pubis and narrow iliac wings.
    • Coxa valga or coxa vara deformity may also develop.
    • Spina bifida occulta is present in some cases.

Treatment

Around 5 years of age, surgical correction may be necessary to prevent any worsening of the deformity.[11] If the mother has dysplasia, caesarian delivery is necessary. Craniofacial surgery may be necessary to correct skull defects.[16] 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.[8] In case of open fontanelle, appropriate headgear may be advised by orthopedist for protection from injury.

Epidemiology

The incidence is estimated at 1:200,000.[16]

References

  1. http://www.nlm.nih.gov/archive/20061212/mesh/jablonski/cgi/jablonski/syndrome_cgi237f.html?term=cleidocranial+dysostosis&field=name Missing or empty |title= (help)
  2. "International nomenclature of constitutional diseases of bone. Revision--May, 1977". J Pediatr. 93 (4): 614–6. 1978. PMID 702238. Unknown parameter |month= ignored (help)
  3. Goodman, RM.; Tadmor, R.; Zaritsky, A.; Becker, SA. (1975). "Evidence for an autosomal recessive form of cleidocranial dysostosis". Clin Genet. 8 (1): 20–9. PMID 1149318. Unknown parameter |month= ignored (help)
  4. LASKER, GW. (1946). "The inheritance of cleidocranial dysostosis". Hum Biol. 18 (2): 103–26. PMID 20285001. Unknown parameter |month= ignored (help)
  5. Zackai, EH.; Robin, NH.; McDonald-McGinn, DM. (1997). "Sibs with cleidocranial dysplasia born to normal parents: germ line mosaicism?". Am J Med Genet. 69 (4): 348–51. PMID 9098480. Unknown parameter |month= ignored (help)
  6. Pal, T.; Napierala, D.; Becker, TA.; Loscalzo, M.; Baldridge, D.; Lee, B.; Sutphen, R. (2007). "The presence of germ line mosaicism in cleidocranial dysplasia". Clin Genet. 71 (6): 589–91. doi:10.1111/j.1399-0004.2007.00812.x. PMID 17539909. Unknown parameter |month= ignored (help)
  7. Mundlos, S.; Otto, F.; Mundlos, C.; Mulliken, JB.; Aylsworth, AS.; Albright, S.; Lindhout, D.; Cole, WG.; Henn, W. (1997). "Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia". Cell. 89 (5): 773–9. PMID 9182765. Unknown parameter |month= ignored (help)
  8. 8.0 8.1 8.2 8.3 Turek's Orthopaedics: Principles And Their Application. Lippincott Williams & Wilkins. 2005. pp. 251–252. ISBN 9780781742986.
  9. http://www.ncbi.nlm.nih.gov/gene/860 Missing or empty |title= (help)
  10. Garg RK, Agrawal P (2008). "Clinical spectrum of cleidocranial dysplasia: a case report". Cases J. 1 (1): 377. doi:10.1186/1757-1626-1-377. PMC 2614945. PMID 19063717.
  11. 11.0 11.1 Hefti, Fritz (2007). Pediatric Orthopedics in Practice. Springer. p. 478. ISBN 9783540699644.
  12. 12.0 12.1 Juhl, John (1998). Paul and Juhl's essentials of radiologic imaging, 7th ed. Lippincott-Raven. ISBN 9780397584215.
  13. Textbook of Radiology and Imaging: Volume 2, 7e. Elsevier Science Health Science Division. 2003. p. 1539. ISBN 9780443071096.
  14. Greene, Walter (2006). Netter's Orthopaedics, 1st ed. Masson. ISBN 9781929007028.
  15. Vanderwerf, Sally (1998). Elsevier's medical terminology for the practicing nurse. Elsevier. p. 65. ISBN 9780444824707.
  16. 16.0 16.1 16.2 Lovell, Wood (2006). Lovell & Winter's Pediatric Orthopaedics, 6e. Lippincott Williams & Wilkins. p. 240. ISBN 9780781753586.

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