Freeman-Sheldon Syndrome - Distal Arthrogryposis Type 2A

FSS, Craniocarpotarsal Dysplasia, Whistling Face

  • Diagnosis
  • Background
  • Lab Tests
  • References

Indications for Testing

Clinical presentation compatible with Freeman-Sheldon syndrome (FSS)

Laboratory Testing

  • FSS (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)

Freeman-Sheldon syndrome (FSS), also known as distal arthrogryposis type 2A, is a rare form of the multiple congenital contracture (arthrogryposis) syndromes. It is characterized by facial muscle contractures (“whistler appearance”) and skeletal or 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 in individuals >30 years
  • Sex – M:F, equal

Inheritance

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

Pathophysiology

MYH3 mutations affect structure of myosin head near adenosine 5'-triphosphate (ATP)-binding sites, which disrupts 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
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.

Freeman-Sheldon Syndrome (MYH3) Sequencing Exon 17 2002662
Method: Polymerase Chain Reaction/Sequencing

Limitations 

Diagnostic errors can occur due to rare sequence variations

Mutations outside exon 17 will not be detected

General References

Ashish J, Muralidhar R, Vijayalakshmi P, Meenakshi S. Freeman-Sheldon syndrome: case report and review of the literature. Int Ophthalmol. 2011; 31(5): 405-7. PubMed

John Hopkins University. Online Mendelian Inheritance in Man, OMIM 193700 - Arthrogryposis, Distal, Type 2A; DA2A. Baltimore, MD [Updated Nov 2016; Accessed: Jul 2017]

National Organization for Rare Disorders, ed. NORD Guide to Rare Disorders, 3, illustrated ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2003.

Stevenson DA, Carey JC, Palumbos J, Rutherford A, Dolcourt J, Bamshad MJ. Clinical characteristics and natural history of Freeman-Sheldon syndrome. Pediatrics. 2006; 117(3): 754-62. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Toydemir RM, Bamshad MJ. Sheldon-Hall syndrome. Orphanet J Rare Dis. 2009; 4: 11. PubMed

Toydemir RM, Rutherford A, Whitby FG, Jorde LB, Carey JC, Bamshad MJ. Mutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndrome. Nat Genet. 2006; 38(5): 561-5. PubMed

Medical Reviewers

Last Update: July 2017