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Genetics Home Reference: your guide to understanding genetic conditions
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Craniometaphyseal dysplasia

Reviewed February 2009

What is craniometaphyseal dysplasia?

Craniometaphyseal dysplasia is a rare condition characterized by progressive thickening of bones in the skull (cranium) and abnormalities at the ends of long bones in the limbs (metaphyseal dysplasia). Except in the most severe cases, the lifespan of people with craniometaphyseal dysplasia is normal.

Bone overgrowth in the head causes many of the signs and symptoms of craniometaphyseal dysplasia. Affected individuals typically have distinctive facial features such as a wide nasal bridge, a prominent forehead, wide-set eyes (hypertelorism), and a prominent jaw. Excessive new bone formation (hyperostosis) in the jaw can delay teething (dentition) or result in absent (non-erupting) teeth. Infants with this condition may have breathing or feeding problems caused by narrow nasal passages. In severe cases, abnormal bone growth can compress the nerves that emerge from the brain and extend to various areas of the head and neck (cranial nerves). Compression of the cranial nerves can lead to paralyzed facial muscles (facial nerve palsy), blindness, or deafness.

The x-rays of individuals with craniometaphyseal dysplasia show unusually shaped long bones, particularly the large bones in the legs. The ends of these bones (metaphyses) are wider and appear less dense in people with this condition.

There are two types of craniometaphyseal dysplasia, which are distinguished by their pattern of inheritance. They are known as the autosomal dominant and autosomal recessive types. Autosomal recessive craniometaphyseal dysplasia is typically more severe than the autosomal dominant form.

How common is craniometaphyseal dysplasia?

Craniometaphyseal dysplasia is a very rare disorder; its incidence is unknown.

What genes are related to craniometaphyseal dysplasia?

Mutations in the ANKH gene cause autosomal dominant craniometaphyseal dysplasia. The ANKH gene provides instructions for making a protein that is present in bone and transports a molecule called pyrophosphate out of cells. Pyrophosphate helps regulate bone formation by preventing mineralization, the process by which minerals such as calcium and phosphorus are deposited in developing bones. The ANKH protein may have other, unknown functions.

Mutations in the ANKH gene that cause autosomal dominant craniometaphyseal dysplasia may decrease the ANKH protein's ability to transport pyrophosphate out of cells. Reduced levels of pyrophosphate can increase bone mineralization, contributing to the bone overgrowth seen in craniometaphyseal dysplasia. Why long bones are shaped differently and only the skull bones become thicker in people with this condition remains unclear.

The genetic cause of autosomal recessive craniometaphyseal dysplasia is unknown. Researchers believe that mutations in an unidentified gene on chromosome 6 may be responsible for the autosomal recessive form of this condition.

Related Gene(s)

Changes in this gene are associated with craniometaphyseal dysplasia.

  • ANKH

How do people inherit craniometaphyseal dysplasia?

Craniometaphyseal dysplasia can have different inheritance patterns. In most cases this condition is inherited in an autosomal dominant pattern, which means one altered copy of the ANKH gene in each cell is sufficient to cause the disorder. Individuals with autosomal dominant craniometaphyseal dysplasia typically have one parent who also has the condition. Less often, cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Rarely, craniometaphyseal dysplasia is suspected to have autosomal recessive inheritance when unaffected parents have more than one child with the condition. Autosomal recessive disorders are caused by mutations in both copies of a gene in each cell. The parents of an individual with an autosomal recessive condition each carry one copy of a mutated gene, but they typically do not show signs and symptoms of the disorder.

Where can I find information about diagnosis or management of craniometaphyseal dysplasia?

These resources address the diagnosis or management of craniometaphyseal dysplasia and may include treatment providers.

  • Gene Review: Craniometaphyseal Dysplasia, Autosomal Dominant (http://www.ncbi.nlm.nih.gov/books/NBK1461)
  • Genetic Testing Registry: Craniometaphyseal dysplasia, autosomal dominant (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1852502)
  • Genetic Testing Registry: Craniometaphyseal dysplasia, autosomal recessive type (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1857496)
  • MedlinePlus Encyclopedia: Facial Paralysis (http://www.nlm.nih.gov/medlineplus/ency/article/003028.htm)

You might also find information on the diagnosis or management of craniometaphyseal dysplasia in Educational resources (http://ghr.nlm.nih.gov/condition/craniometaphyseal-dysplasia/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/craniometaphyseal-dysplasia/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about craniometaphyseal dysplasia?

You may find the following resources about craniometaphyseal dysplasia helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for craniometaphyseal dysplasia?

  • Autosomal dominant craniometaphyseal dysplasia
  • Autosomal recessive craniometaphyseal dysplasia
  • CMD
  • CMDD
  • CMDJ
  • CMDR
  • Craniometaphyseal dysplasia, Jackson type

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about craniometaphyseal dysplasia?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/gard).

What glossary definitions help with understanding craniometaphyseal dysplasia?

autosomal ; autosomal dominant ; autosomal recessive ; bone formation ; bone mineralization ; calcium ; cell ; chromosome ; compression ; cranial nerves ; dysplasia ; gene ; hyperostosis ; hypertelorism ; incidence ; inheritance ; inherited ; molecule ; palsy ; pattern of inheritance ; phosphorus ; protein ; recessive ; x-rays

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Addison WN, Azari F, Sørensen ES, Kaartinen MT, McKee MD. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007 May 25;282(21):15872-83. Epub 2007 Mar 23. (http://www.ncbi.nlm.nih.gov/pubmed/17383965?dopt=Abstract)
  • Gene Review: Craniometaphyseal Dysplasia, Autosomal Dominant (http://www.ncbi.nlm.nih.gov/books/NBK1461)
  • Iughetti P, Alonso LG, Wilcox W, Alonso N, Passos-Bueno MR. Mapping of the autosomal recessive (AR) craniometaphyseal dysplasia locus to chromosome region 6q21-22 and confirmation of genetic heterogeneity for mild AR spondylocostal dysplasia. Am J Med Genet. 2000 Dec 18;95(5):482-91. (http://www.ncbi.nlm.nih.gov/pubmed/11146471?dopt=Abstract)
  • Nürnberg P, Thiele H, Chandler D, Höhne W, Cunningham ML, Ritter H, Leschik G, Uhlmann K, Mischung C, Harrop K, Goldblatt J, Borochowitz ZU, Kotzot D, Westermann F, Mundlos S, Braun HS, Laing N, Tinschert S. Heterozygous mutations in ANKH, the human ortholog of the mouse progressive ankylosis gene, result in craniometaphyseal dysplasia. Nat Genet. 2001 May;28(1):37-41. (http://www.ncbi.nlm.nih.gov/pubmed/11326272?dopt=Abstract)
  • Reichenberger E, Tiziani V, Watanabe S, Park L, Ueki Y, Santanna C, Baur ST, Shiang R, Grange DK, Beighton P, Gardner J, Hamersma H, Sellars S, Ramesar R, Lidral AC, Sommer A, Raposo do Amaral CM, Gorlin RJ, Mulliken JB, Olsen BR. Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the transmembrane protein ANK. Am J Hum Genet. 2001 Jun;68(6):1321-6. Epub 2001 Apr 16. (http://www.ncbi.nlm.nih.gov/pubmed/11326338?dopt=Abstract)
  • Zaka R, Williams CJ. Role of the progressive ankylosis gene in cartilage mineralization. Curr Opin Rheumatol. 2006 Mar;18(2):181-6. Review. (http://www.ncbi.nlm.nih.gov/pubmed/16462526?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: February 2009
Published: January 27, 2015