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Disease Profile

Craniometaphyseal dysplasia, autosomal recessive type

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

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ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

CMDR

Categories

Congenital and Genetic Diseases; Musculoskeletal Diseases

Summary

Autosomal recessive craniometaphyseal dysplasia is a genetic skeletal condition characterized by progressive thickening of bones in the skull (cranium) and abnormalities at the ends of long bones in the limbs (metaphyseal dysplasia). The overgrowth of bone in the head can lead to distinctive facial features and delayed tooth eruption, as well as compression of the cranial nerves.[1] The condition is caused by mutations in the GJA1 gene. As the name suggests, it is inherited in an autosomal recessive manner.[2] Treatment is symptomatic and supportive, and may include surgery to relieve cranial pressure and correct facial deformities.[3]

Symptoms

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 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.[1]

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.[1]

The symptoms seen in autosomal recessive craniometaphyseal dysplasia are typically more severe than those seen in the autosomal dominant form.[1]

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormality of the metaphysis
Abnormality of the wide portion of a long bone
0000944
Craniofacial hyperostosis
Excessive bone growth of the skull and face
0004493
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Osteopetrosis
Harder, denser, fracture-prone bones
0011002
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
30%-79% of people have these symptoms
Skeletal dysplasia
0002652
Telecanthus
Corners of eye widely separated
0000506
5%-29% of people have these symptoms
Conductive hearing impairment
Conductive deafness
Conductive hearing loss

[ more ]

0000405
Facial palsy
Bell's palsy
0010628
Sensorineural hearing impairment
0000407
Visual impairment
Impaired vision
Loss of eyesight
Poor vision

[ more ]

0000505
Percent of people who have these symptoms is not available through HPO
Abnormal nasopharynx morphology
0001739
Abnormal thorax morphology
Abnormality of the chest
0000765
Autosomal recessive inheritance
0000007
Bony paranasal bossing
0004407
Broad alveolar ridges
0000187
Club-shaped distal femur
Club-shaped outermost end of thighbone
0006384
Coarse facial features
Coarse facial appearance
0000280
Delayed eruption of permanent teeth
Delayed eruption of adult teeth
0000696
Facial hyperostosis
Enlargment of the facial bones
Excessive growth of facial bones
Excessive growth of facial skeleton
Increase in size of the facial bones
Overgrowth of facial bones
Overgrowth of facial skeleton
Overgrowth of the facial bones

[ more ]

0005465
Flared metaphysis
Flared wide portion of long bone
0003015
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Mandibular prognathia
Big lower jaw
Increased projection of lower jaw
Increased size of lower jaw
Large lower jaw
Prominent chin
Prominent lower jaw

[ more ]

0000303
Metaphyseal dysplasia
0100255
Mixed hearing impairment
Hearing loss, mixed
Mixed hearing loss

[ more ]

0000410
Nasal obstruction
Blockage of nose
Nasal blockage
Obstruction of nose
Stuffy nose

[ more ]

0001742
Optic atrophy
0000648
Patchy sclerosis of finger phalanx
Uneven increase in bone density in finger bone
0009772

Cause

Autosomal recessive craniometaphyseal dysplasia is caused by mutations in the GJA1 gene.[2] The GJA1 gene provides instructions for making a protein called connexin43, which is one of 21 connexin proteins in humans. Connexins lay a role in cell-to-cell communication by forming channels, or gap junctions, between cells. Gap junctions allow for the transport of nutrients, charged particles (ions), and other small molecules that carry necessary communication signals between cells. Connexin43 is found in many human tissues, including eyes, skin, bine, ears, heart, and brain.[4]

Mutations in the GJA1 gene that cause autosomal recessive craniometaphyseal dysplasia appear to disrupt bone remodeling. The exact mechanism involved is yet to be determined.[5]

Treatment

Treatment consists primarily of surgery to reduce compression of cranial nerves and the brain stem/spinal cord at the level of the foramen magnum. Severely overgrown facial bones can be contoured; however, surgical procedures can be technically difficult and bone regrowth is common. Individuals with craniometaphyseal dysplasia should have regular neurologic evaluations, hearing assessments, and ophthalmologic examinations. The frequency of these evaluations and assessments should be determined by the individual's history and severity of skeletal changes.[6]

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Craniometaphyseal dysplasia, autosomal recessive type. This website is maintained by the National Library of Medicine.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Craniometaphyseal dysplasia, autosomal recessive type. Click on the link to view a sample search on this topic.

References

  1. Craniometaphyseal dysplasia. Genetics Home Reference (GHR). February 2009; https://ghr.nlm.nih.gov/condition/craniometaphyseal-dysplasia.
  2. CRANIOMETAPHYSEAL DYSPLASIA, AUTOSOMAL RECESSIVE. Online Mendelian Inheritance in Man (OMIM). September 6, 2013; https://www.omim.org/entry/218400.
  3. Craniometaphyseal Dysplasia. National Organization for Rare Disorders (NORD). 2005; https://rarediseases.org/rare-diseases/craniometaphyseal-dysplasia/.
  4. GJA1. Genetics Home Reference (GHR). February 2009; https://ghr.nlm.nih.gov/gene/GJA1.
  5. Hu, Y., Chen, I., de Almeida, S., Tiziani, V., Raposo Do Amaral, C. M., Gowrishankar, K., Passos-Bueno, M. R., Reichenberger, E. J. A novel autosomal recessive GJA1 missense mutation linked to Craniometaphyseal dysplasia. PLoS One. August 12; 8(8):e73576. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741164/.
  6. Reichenberger E, Chen IP. Craniometaphyseal Dysplasia, Autosomal Dominant. GeneReviews. January 15, 2015; https://www.ncbi.nlm.nih.gov/books/NBK1461/.

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