Clinical characteristics: Autosomal dominant craniometaphyseal dysplasia (designated AD-CMD in this review) is characterized by progressive diffuse hyperostosis of cranial bones evident clinically as wide nasal bridge, paranasal bossing, widely spaced eyes with an increase in bizygomatic width, and prominent mandible. Development of dentition may be delayed and teeth may fail to erupt as a result of hyperostosis and sclerosis of alveolar bone. Progressive thickening of craniofacial bones continues throughout life, often resulting in narrowing of the cranial foramina, including the foramen magnum. If untreated, compression of cranial nerves can lead to disabling conditions such as facial palsy, blindness, or deafness (conductive and/or sensorineural hearing loss). In individuals with typical uncomplicated AD-CMD life expectancy is normal; in those with severe AD-CMD life expectancy can be reduced as a result of compression of the foramen magnum.
Diagnosis/testing: Diagnosis is based on clinical and radiographic findings that include diffuse hyperostosis of the cranial base, cranial vault, facial bones, and mandible as well as widening and radiolucency of metaphyses in long bones. Identification of a heterozygous pathogenic variant in ANKH by molecular genetic testing can confirm the diagnosis if clinical features are inconclusive.
Management: Treatment of manifestations: 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.
Surveillance: Evaluation for feeding and respiratory issues at least annually. Neurologic evaluation for signs and symptoms of narrowing of the cranial foramina including the foramen magnum at least annually. Hearing and ophthalmologic assessment at least annually.
Genetic counseling: By definition, AD-CMD is inherited in an autosomal dominant manner. Most individuals diagnosed with AD-CMD have an affected parent; the proportion of individuals with AD-CMD caused by a de novo pathogenic variant is thought to be very low. Each child of an individual with AD-CMD has a 50% chance of inheriting the pathogenic variant. Once the AD-CMD-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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