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
Test Name and Number Recommended Use Limitations Follow Up
Freeman-Sheldon Syndrome (MYH3) Sequencing Exon 17 2002662
Method: Polymerase Chain Reaction/Sequencing

Confirm clinical diagnosis of FSS

Only detects exon 17 mutations

Rare diagnostic errors can occur due to primer site mutations