Craniometaphyseal dysplasia, autosomal dominant

Alternate names

CMDD; CMD; CMDJ; Craniometaphyseal dysplasia Jackson type

Definition

Autosomal dominant 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).

Epidemiology

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

Cause

• Autosomal dominant craniometaphyseal dysplasia is caused by mutations in the ANKH gene.
• The ANKH gene provides instructions for making a protein that plays a role in the development and function of cells that build bones (osteoblasts) and cells that break down bone (osteoclasts).
• Osteoclasts are involved in bone remodeling, a normal process in which old bone is removed and new bone is created to replace it.
• In addition, the ANKH protein transports a molecule called pyrophosphate out of cells.
• The pyrophosphate found outside of cells (extracellular pyrophosphate) helps control 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.

Gene mutations

• Mutations in the ANKH gene that cause autosomal dominant craniometaphyseal dysplasia impair the maturation (differentiation) of osteoclasts, which likely disrupts bone remodeling.
• Reduced breakdown of bone tissue can contribute to the bone thickening characteristic of craniometaphyseal dysplasia.
• ANKH gene mutations may also reduce the protein's ability to transport pyrophosphate out of cells.
• A shortage of extracellular pyrophosphate can increase bone mineralization, which may also contribute to the bone abnormalities.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

When caused by mutations in the ANKH gene, craniometaphyseal dysplasia follows 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.

Signs and 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.
• 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Abnormality of the metaphysis(Abnormality of the wide portion of a long bone)
• Craniofacial hyperostosis(Excessive bone growth of the skull and face)
• Depressed nasal bridge(Depressed bridge of nose)
• Hypertelorism(Wide-set eyes)
• Osteopetrosis(Harder, denser, fracture-prone bones)
• Wide nasal bridge(Broad nasal bridge)

30%-79% of people have these symptoms

• Skeletal dysplasia
• Telecanthus(Corners of eye widely separated)

5%-29% of people have these symptoms

• Conductive hearing impairment(Conductive deafness)
• Facial palsy(Bell's palsy)
• Sensorineural hearing impairment
• Visual impairment(Impaired vision)

Diagnosis

AD-CMD should be suspected in individuals with the following clinical, radiographic, and laboratory features.[1].

Clinical features

• Obstruction of the nasal sinuses
• Characteristic facial features. Wide nasal bridge, paranasal bossing, hypertelorism with an increase in bizygomatic width, and prominent mandible.
• Dolichocephaly due to fronto-occipital hyperostosis

Radiographic features

• Cranial base. Sclerosis may begin in infancy. Increasing diffuse hyperostosis of the cranial base leads to narrowing of the foramen magnum.
• Skull. Diffuse hyperostosis of cranial vault, facial bones, and mandible increases as the condition progresses with obstruction of the cranial foramina.
• Long bones. Metaphyseal widening (described as Erlenmeyer flask- or club-shaped) with thinned cortex and decreased bony density in the metaphyses can be detected early in life. Metaphyseal changes typically develop during early childhood. The flaring is most prominent in the distal femur and tibia .
• Diaphyseal sclerosis/hyperostosis can be present in infancy but disappears with age.
• Bone density of the diaphyses is normal in children and adults; cortical thickness can be increased.
• Ribs and clavicles (medial portion [i.e., endochondral]) can be sclerotic in younger children but show normal bone density by age five years

The diagnosis of AD-CMD is established in a proband with characteristic craniofacial hyperostosis and flaring and undertrabeculation of long bone metaphyses and/or a heterozygous pathogenic variant in ANKH identified by molecular genetic testing.

Treatment

• Treatment for feeding and respiratory issues per craniofacial team
• Surgical intervention 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.
• Hearing aids; vision aids and surgical treatment for optic nerve impaction; speech therapy; surgical intervention for malocclusion.[2].

NIH genetic and rare disease info

• NIH info on Craniometaphyseal dysplasia, autosomal dominant

Craniometaphyseal dysplasia, autosomal dominant is a rare disease.

Craniometaphyseal dysplasia, autosomal dominant Resources
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