The Phenotypic Spectrum of Miller Syndrome: Insight From a French Cohort

Miller syndrome (MIM#263750) is a rare autosomal recessive acrofacial dysostosis associated with biallelic DHODH variants. Since the identification of the gene in 2010, five case reports have described a variable phenotype in only nine individuals from eight families. We present a cohort of 10 individuals from seven families affected by Miller syndrome, spanning the prenatal stage to 46 years of age. We report on the largest cohort of Miller syndrome to date, which highlights novel findings, including optic atrophy in multiple members of one consanguineous family. The typical postaxial limb defects, including the absence of the 5th digit, were consistent with prior descriptions, but we highlighted the frequent involvement of preaxial structures (thumb and tibial hypoplasia). A higher incidence of camptodactyly and the presence of facial nevus in two patients were notable findings. Congenital heart defects, primarily atrial septal defects, were common, and all living individuals had normal neurodevelopment. This cohort expands the phenotypic spectrum of Miller syndrome associated with variation in DHODH, presenting new findings such as preaxial involvement and facial nevus simplex. Optic atrophy in one family could prompt screening of other cases. Early prenatal diagnosis, particularly in the presence of cardinal limb and cardiac malformations, is crucial for management and genetic counseling.