Postaxial acrofacial dysostosis

Postaxial acrofacial dysostosis, also known as Miller syndrome or Genée-Wiedemann syndrome, is a rare genetic disorder characterized by distinctive craniofacial abnormalities combined with limb defects, particularly affecting the postaxial (ulnar/fibular) side of the extremities. It belongs to the group of acrofacial dysostoses, conditions that involve both facial and limb malformations. The craniofacial features include malar (cheekbone) hypoplasia, downslanting palpebral fissures, micrognathia (small lower jaw), cleft lip and/or cleft palate, coloboma (notching) of the lower eyelids, and cup-shaped or absent ears with associated conductive hearing loss. The limb abnormalities predominantly affect the postaxial rays and may include absence or hypoplasia of the fifth digits, shortening of the ulna and radius, and abnormalities of the fourth and fifth toes. Some patients may also have syndactyly or other skeletal anomalies. Miller syndrome is caused by biallelic pathogenic variants in the DHODH gene, which encodes dihydroorotate dehydrogenase, an enzyme essential for de novo pyrimidine biosynthesis. This was notably one of the first Mendelian disorders identified through exome sequencing. The condition is present at birth and severity can vary considerably among affected individuals. Management is multidisciplinary and symptomatic, involving craniofacial surgery for jaw and palate abnormalities, reconstructive surgery for limb defects, hearing aids or surgical correction for hearing loss, and speech therapy. Regular monitoring by a team including geneticists, plastic surgeons, orthopedic specialists, audiologists, and speech-language pathologists is recommended. There is currently no cure or disease-specific therapy available.

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