Freeman-Sheldon Syndrome - Distal Arthrogryposis Type 2A

Diagnosis

Indications for Testing

• Clinical presentation compatible with syndrome

Laboratory Testing

• Freeman-Sheldon syndrome (MYH3) sequencing
  • MYH3 mutation detected – predictive of FSS
  • No mutation detected – risk for FSS reduced but not eliminated

Differential Diagnosis

• Sheldon-Hall syndrome
• Distal arthrogryposis type 1
• Trismus-pseudocamptodactyly syndrome
• Congenital contractual arachnodactyly (Beals-Hecht syndrome)

Clinical Background

Freeman-Sheldon syndrome (FSS) is a rare form of the multiple congenital contracture (arthrogryposis) syndromes. It is characterized by facial muscle contractures (“whistler appearance”), skeletal and joint abnormalities.

Epidemiology

• Incidence – rare (~100 cases reported to date)
• Prevalence – appears to be similar across populations but most reported individuals are of European ancestry
• Age – usually diagnosed in childhood; initial diagnosis rare >30 years
• Sex – M:F, equal

Inheritance

• Autosomal dominant inheritance – ~70% of cases represent new mutations
• Mutations in MYH3 gene – 93% of cases
  • Two common missense mutations, c.2014C>T (p.R672C) and c.2015G>A (p.R672H), occur in exon 17 of MYH3 – 72% of FSS cases
• No other FSS-associated genes identified to date

Pathophysiology

• MYH3 mutations affect structure of myosin head near the ATP-binding sites
  • Disrupt the normal function of myosin in muscle contraction

Clinical Presentation

• Craniofacial – facial dysmorphism, strabismus, dental crowding, hearing loss, facial muscle contractures
• Musculoskeletal – scoliosis, restricted cervical flexion, joint contractures of hands, fingers, hips, knees, ankles, feet, and toes
• Genitalia – cryptorchidism, inguinal hernia
• Life threatening respiratory complications common in perinatal and neonatal period

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory