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

Area of Science:

• Genetics
• Developmental Biology
• Rare Diseases

Background:

• Miller syndrome is a rare autosomal recessive acrofacial dysostosis linked to DHODH gene variants.
• Previous reports described a variable phenotype in only nine individuals across eight families.
• This study presents the largest cohort to date, offering expanded insights into Miller syndrome.

Purpose of the Study:

• To describe the clinical spectrum and novel findings in a cohort of 10 individuals with Miller syndrome.
• To expand the understanding of phenotypes associated with DHODH variations.
• To emphasize the importance of early diagnosis and genetic counseling.

Main Methods:

• Clinical evaluation of 10 individuals from seven families with Miller syndrome.
• Phenotypic characterization spanning prenatal to adult stages.
• Review of existing literature on Miller syndrome and DHODH variants.

Main Results:

• The cohort exhibited typical postaxial limb defects (e.g., 5th digit absence) and frequent preaxial involvement (thumb/tibial hypoplasia).
• Novel findings included optic atrophy in a consanguineous family, camptodactyly, and facial nevus simplex.
• Congenital heart defects (mainly atrial septal defects) were common; all living individuals had normal neurodevelopment.

Conclusions:

• This cohort broadens the known phenotypic spectrum of Miller syndrome associated with DHODH variants.
• Optic atrophy and preaxial involvement are significant findings warranting further investigation and screening.
• Early prenatal diagnosis is critical for managing Miller syndrome, especially with limb and cardiac anomalies.