Freeman-Sheldon Syndrome - Distal Arthrogryposis Type 2A

  • Diagnosis
  • Background
  • Lab Tests
  • References

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)

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”), 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 ofMYH3 – 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
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 

Detects mutations only in exon 17 of MYH3 gene

No other mutations will be detected

Rare diagnostic errors can occur due to primer site mutations

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

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

Online Mendelian Inheritance in Man, OMIM 193700 - Arthrogryposis, Distal, Type 2A; DA2A. John Hopkins University. Baltimore, MD [Last edited Jul 2015; Accessed: Nov 2015]

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

Toydemir RM, Bamshad MJ. Sheldon-Hall syndrome. Orphanet J Rare Dis. 2009; 4: 11. 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: August 2016