Arthrogryposis, distal, type 2A (DA2A) is also known as Freeman-Sheldon syndrome (FSS) or whistling face syndrome and is caused by heterozygous mutation in the MYH3 gene. Mutations in this gene can also cause distal arthrogryposis type 2B (also known as Sheldon-Hall syndrome, a genetically heterogeneous subtype of distal arthrogryposis caused also by mutations in the TPM2, TNNT3 or TNNI2 gene), distal arthrogryposis 8 (DA8) and an autosomal dominant form of multiple pterygium syndrome. Intelligence in Freeman-Sheldon syndrome can be normal, but also profound mental retardation has been observed in cases with severe neurological involvement and MRI abnormalities.
Detailed clinical description
DA2A is phenotypically similar to DA1, but, in addition to contractures of the hands and feet, it is characterized by oropharyngeal abnormalities, scoliosis, and a distinctive face that includes a very small oral orifice (often only a few millimeters in diameter at birth), puckered lips, and an H-shaped dimple of the chin; hence, DA2A has been called whistling face syndrome. Facial features are typical of DA2A and are used to make the differential diagnosis with DA1.
More in details, any of the following can be observed in different combinations: camptodactyly with ulnar deviation, talipes equinovarus, clubfoot, Severe skew foot, congenital windmill vane position of the hand, abnormal x-ray appearance of the floor of the anterior cranial fossa of the skull, deep-sunken eyes with hypertelorism, increased philtrum length, small nose and nostrils, micrognathia, blepharophimosis, ptosis, short stature, proximal and distal joint contractures, failure to thrive, hypotonia, profound mental retardation, strabismus, hearing loss and, of course, small mouth.
In cases with profound neurological involvement, which are thought to be more often autosomal recessive and likely due to mutations in as yet unknown genes, MRI scan can show generalized cerebral, cerebellar, and brainstem atrophy. Bilateral juvenile glaucoma has been reported in one case. Malignant hyperthermia and hyperpyrexia can arise in some as anesthetic and/or surgical complications.
The syndrome has been reported in multigenerational families, also with reduced penetrance.
Cases with whistling face without limb involvement have been described.
DA2A is caused by mutations in the MYH3 gene. Mutations so far reported include the two mutations in exon 17, c.2084G>A (p.Arg672His) and c.2083C>T (p.Arg672Cys), the latter impairing cross-bridge detachment and cycling in adult skeletal muscle, c.602C>T (p. Thr178Ile) in exon 5, and two mutations in exon 21, c.2543T>A (Val825Asp) and c.2590_2592delCTC. Germline mosaicism for MYH3 mutations has been proved. The transmission of MYH3-related Freeman-Sheldon syndrome is autosomal dominant, although some authors invoke the possibility of autosomal recessive inheritance likely due to mutations in as yet unknown genes, especially when severe neurologic involvement is diagnosed (see also OMIM 277720).
Genetic testing strategy
Targeted mutation analysis can be done to detect known disease-causing mutations in MYH3. However, since arthrogryposes are genetically and clinically heterogeneous, full MYH3 gene sequencing (EXOME GENE) or panel testing (EXOME PANEL) is recommended.
Panel testing recommended at Breda Genetics for this condition:
Progressive neurological deterioration in a child with distal arthrogryposis and whistling face. Lev D, Yanoov M, Weintraub S, Lerman-Sagie T. J Med Genet. 2000 Mar;37(3):231-3. PMID 10777369
Molecularly proven mosaicism in phenotypically normal parent of a girl with Freeman-Sheldon Syndrome caused by a pathogenic MYH3 mutation. Hague J, Delon I, Brugger K, Martin H, Abbs S, Park SM. Am J Med Genet A. 2016 Jun;170(6):1608-12. PMID 26996280
Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3. Chong JX, Burrage LC, Beck AE, Marvin CT, McMillin MJ, Shively KM, Harrell TM, Buckingham KJ, Bacino CA, Jain M, Alanay Y, Berry SA, Carey JC, Gibbs RA, Lee BH, Krakow D, Shendure J, Nickerson DA; University of Washington Center for Mendelian Genomics, Bamshad MJ. Am J Hum Genet. 2015 May 7;96(5):841-9. PMID 25957469
The embryonic myosin R672C mutation that underlies Freeman-Sheldon syndrome impairs cross-bridge detachment and cycling in adult skeletal muscle. Racca AW, Beck AE, McMillin MJ, Korte FS, Bamshad MJ, Regnier M. Hum Mol Genet. 2015 Jun 15;24(12):3348-58. PMID 25740846
Severe skew foot deformity in a patient with freeman-sheldon syndrome. Kaissi AA, Klaushofer K, Grill F. J Clin Med Res. 2011 Oct;3(5):265-7. PMID 22383916