Freeman-Sheldon Syndrome
Freeman-Sheldon Syndrome (Whistling Face Syndrome)
Definition: A rare congenital condition characterized by distinctive facial features and distal arthrogryposis, caused by mutations in the MYH3 gene.
Key Points
- Alternative names:
- Cranio-carpo-tarsal dysplasia
- Whistling face-windmill vane hand syndrome
- Distal arthrogryposis type 2A (DA2A)
- Epidemiology:
- Prevalence: < 1 per million births
- No gender or ethnic predilection
- First described in 1938
Historical Perspective
- 1938: First description by Freeman and Sheldon
- 1963: Recognition as distinct syndrome
- 2006: Identification of MYH3 gene mutations
- 2014: Establishment of diagnostic criteria
Clinical Manifestations
Craniofacial Features (>95%)
- Characteristic facial appearance:
- Microstomia (small mouth)
- Pursed lips ("whistling face")
- H-shaped dimpling of chin
- Long philtrum
- High-arched palate
- Additional features:
- Blepharophimosis
- Deep-set eyes
- Prominent nasolabial folds
- Small nose with narrow nostrils
- Masklike facies
Musculoskeletal Manifestations
- Upper extremities:
- Ulnar deviation of fingers
- Camptodactyly
- "Windmill vane" positioning of hands
- Limited wrist mobility
- Thumb-in-palm deformity
- Lower extremities:
- Talipes equinovarus
- Vertical talus
- Calcaneovalgus deformities
- Limited hip mobility
- Spinal involvement:
- Scoliosis (>50%)
- Kyphosis
- Cervical spine abnormalities
Speech and Feeding Issues
- Feeding difficulties:
- Poor sucking reflex
- Swallowing problems
- Failure to thrive
- Gastroesophageal reflux
- Speech problems:
- Dysarthria
- Limited verbal expression
- Voice alterations
Genetics and Pathophysiology
Genetic Basis
- Gene: MYH3 (Embryonic Myosin Heavy Chain)
- Location: Chromosome 17p13.1
- Inheritance: Autosomal dominant
- De novo mutations common
- Mutation spectrum:
- Missense mutations most common
- Hotspot mutations in motor domain
- Variable expressivity
Molecular Mechanisms
- Pathophysiology:
- Abnormal myosin function
- Disrupted muscle development
- Altered contractile properties
- Developmental impact:
- Embryonic muscle formation
- Facial muscle development
- Joint formation
Diagnostic Approach
Clinical Diagnosis
- Major criteria:
- Microstomia
- Whistling face appearance
- H-shaped chin dimpling
- Multiple joint contractures
- Supporting features:
- Characteristic hand positioning
- Foot deformities
- Scoliosis
Required Investigations
- Genetic testing:
- MYH3 gene sequencing
- Deletion/duplication analysis
- Family screening when indicated
- Imaging studies:
- Skeletal survey
- Spine radiographs
- Joint imaging
- Cranial imaging when indicated
- Additional assessments:
- Swallowing evaluation
- Speech assessment
- Respiratory function tests
- Neurological examination
Differential Diagnosis
- Other distal arthrogryposes:
- Sheldon-Hall syndrome (DA2B)
- Gordon syndrome (DA3)
- Multiple pterygium syndrome
- Similar facial phenotypes:
- Schwartz-Jampel syndrome
- Marden-Walker syndrome
- Moebius syndrome
Treatment and Management
Multidisciplinary Care Team
- Core specialists:
- Clinical geneticist
- Orthopedic surgeon
- Plastic surgeon
- Physical therapist
- Speech pathologist
- Feeding specialist
- Supporting specialists:
- Respiratory physician
- Neurologist
- Occupational therapist
- Psychologist
Specific Interventions
- Early intervention:
- Feeding support
- Physical therapy
- Speech therapy
- Occupational therapy
- Surgical management:
- Timing considerations
- Staged approach
- Common procedures:
- Commissuroplasty
- Hand surgery
- Foot reconstruction
- Spinal fusion when needed
Complications and Monitoring
Common Complications
- Respiratory:
- Sleep apnea
- Restrictive lung disease
- Recurrent respiratory infections
- Feeding/Growth:
- Malnutrition
- Growth delays
- Aspiration risk
- Musculoskeletal:
- Progressive scoliosis
- Joint contractures
- Limited mobility
Monitoring Protocol
- Regular assessments:
- Growth monitoring
- Developmental evaluation
- Respiratory function
- Musculoskeletal status
- Frequency of follow-up:
- Monthly in infancy
- Quarterly in early childhood
- Annually or as needed later
Clinical Research and Advances
Current Research
- Areas of focus:
- Genotype-phenotype correlations
- Novel therapeutic approaches
- Long-term outcomes
- Quality of life studies
- Clinical trials:
- Surgical techniques
- Physical therapy protocols
- Treatment outcomes
Future Directions
- Therapeutic development:
- Targeted molecular therapies
- Novel surgical approaches
- Improved rehabilitation methods
- Research needs:
- Natural history studies
- Biomarker development
- Treatment optimization
